Persistent Joint Pain Following Arthropod Virus Infections.

PURPOSE OF REVIEW: Persistent joint pain is a common manifestation of arthropod-borne viral infections and can cause long-term disability. We review the epidemiology, pathophysiology, diagnosis, and management of arthritogenic alphavirus infection. RECENT FINDINGS: The global re-emergence of alphaviral outbreaks has led to an increase in virus-induced arthralgia and arthritis. Alphaviruses, including Chikungunya, O'nyong'nyong, Sindbis, Barmah Forest, Ross River, and Mayaro viruses, are associated with acute and/or chronic rheumatic symptoms. Identification of Mxra8 as a viral entry receptor in the alphaviral replication pathway creates opportunities for treatment and prevention. Recent evidence suggesting virus does not persist in synovial fluid during chronic chikungunya infection indicates that immunomodulators may be given safely. The etiology of persistent joint pain after alphavirus infection is still poorly understood. New diagnostic tools along and evidence-based treatment could significantly improve morbidity and long-term disability.

Use of BioFire FilmArray gastrointestinal PCR panel associated with reductions in antibiotic use, time to optimal antibiotics, and length of stay.

BACKGROUND: Rapid and accurate diagnostic tools are needed for appropriate management of infectious diarrhea. METHODS: We evaluated the impact of the introduction of rapid multiplex PCR testing using the FilmArray gastrointestinal (GI) panel (BioFire Diagnostics, LLC, Salt Lake City, UT) at our institution, and compared the results to those of standard stool cultures. RESULTS: The most common pathogens detected by the FilmArray GI panel were Clostridium difficile (55.0%), Campylobacter species (20.9%), Salmonella species (12.4%), and Shigella/EIEC species (12.4%). Rates of reproducibility in stool culture for these pathogens ranged from 56.3 to 77.8%. Co-detection of two or more organisms was common (24.2%), most commonly involving EPEC, EAEC, ETEC, and STEC. The time from arrival in the Emergency Department to discharge or admission to the hospital was unchanged after the introduction of FilmArray GI panel, but length of hospital stay was shorter (3 vs. 7.5 days, p = 0.0002) for the FilmArray group. The time to empiric antibiotics did not differ significantly, but optimal antibiotics were started earlier after introduction of the FilmArray GI panel (hospital day 1 vs. 2, p < 0.0001). More patients were discharged without antibiotics after introduction of the FilmArray GI panel (14.0% vs. 4.5%; p < 0.001). CONCLUSION: Our results demonstrate that the FilmArray GI panel is an important tool for improving both patient care and antibiotic stewardship, despite the tendency for positive results with multiple pathogens.

Augmented Zika and Dengue Neutralizing Antibodies Are Associated With Guillain-Barré Syndrome.

The role of neutralizing antibodies in Zika-induced Guillain-Barré syndrome (GBS) has not yet been investigated. We conducted a case-control study using sera from the 2016 Zika epidemic in Colombia to determine the neutralizing antibody activity against Zika virus (ZIKV) and dengue virus serotype 2 (DENV2). We observed increased neutralizing antibody titers against DENV2 in ZIKV-infected individuals compared with uninfected controls and higher titers to both ZIKV and DENV2 in ZIKV-infected patients diagnosed with GBS compared with non-GBS ZIKV-infected controls. These data suggest that high neutralizing antibody titers to DENV and to ZIKV are associated with GBS during ZIKV infection.

The effects of cocaine on HIV transcription.

Illicit drug users are a high-risk population for infection with the human immunodeficiency virus (HIV). A strong correlation exists between prohibited drug use and an increased rate of HIV transmission. Cocaine stands out as one of the most frequently abused illicit drugs, and its use is correlated with HIV infection and disease progression. The central nervous system (CNS) is a common target for both drugs of abuse and HIV, and cocaine intake further accelerates neuronal injury in HIV patients. Although the high incidence of HIV infection in illicit drug abusers is primarily due to high-risk activities such as needle sharing and unprotected sex, several studies have demonstrated that cocaine enhances the rate of HIV gene expression and replication by activating various signal transduction pathways and downstream transcription factors. In order to generate mature HIV genomic transcript, HIV gene expression has to pass through both the initiation and elongation phases of transcription, which requires discrete transcription factors. In this review, we will provide a detailed analysis of the molecular mechanisms that regulate HIV transcription and discuss how cocaine modulates those mechanisms to upregulate HIV transcription and eventually HIV replication.

Single-molecule long-read 16S sequencing to characterize the lung microbiome from mechanically ventilated patients with suspected pneumonia.

In critically ill patients, the development of pneumonia results in significant morbidity and mortality and additional health care costs. The accurate and rapid identification of the microbial pathogens in patients with pulmonary infections might lead to targeted antimicrobial therapy with potentially fewer adverse effects and lower costs. Major advances in next-generation sequencing (NGS) allow culture-independent identification of pathogens. The present study used NGS of essentially full-length PCR-amplified 16S ribosomal DNA from the bronchial aspirates of intubated patients with suspected pneumonia. The results from 61 patients demonstrated that sufficient DNA was obtained from 72% of samples, 44% of which (27 samples) yielded PCR amplimers suitable for NGS. Out of the 27 sequenced samples, only 20 had bacterial culture growth, while the microbiological and NGS identification of bacteria coincided in 17 (85%) of these samples. Despite the lack of bacterial growth in 7 samples that yielded amplimers and were sequenced, the NGS identified a number of bacterial species in these samples. Overall, a significant diversity of bacterial species was identified from the same genus as the predominant cultured pathogens. The numbers of NGS-identifiable bacterial genera were consistently higher than identified by standard microbiological methods. As technical advances reduce the processing and sequencing times, NGS-based methods will ultimately be able to provide clinicians with rapid, precise, culture-independent identification of bacterial, fungal, and viral pathogens and their antimicrobial sensitivity profiles.

Cytokine and T cell responses in post-chikungunya viral arthritis: A cross-sectional study.

OBJECTIVE: To define the relationship between chronic chikungunya post-viral arthritis disease severity, cytokine response and T cell subsets in order to identify potential targets for therapy. METHODS: Participants with chikungunya arthritis were recruited from Colombia from 2019-2021. Arthritis disease severity was quantified using the Disease Activity Score-28 and an Arthritis-Flare Questionnaire adapted for chikungunya arthritis. Plasma cytokine concentrations (interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ and tumor necrosis factor (TNF)) were measured using a Meso Scale Diagnostics assay. Peripheral blood T cell subsets were measured using flow cytometry. RESULTS: Among participants with chikungunya arthritis (N = 158), IL-2 levels and frequency of regulatory T cells (Tregs) were low. Increased arthritis disease activity was associated with higher levels of inflammatory cytokines (IL-6, TNF and CRP) and immunoregulatory cytokine IL-10 (p<0.05). Increased arthritis flare activity was associated with higher Treg frequencies (p<0.05) without affecting T effector (Teff) frequencies, Treg/Teff ratios and Treg subsets. Finally, elevated levels of IL-2 were correlated with increased Treg frequency, percent Tregs out of CD4+ T cells, and Treg subsets expressing immunosuppressive markers, while also correlating with an increased percent Teff out of live lymphocytes (p<0.05). CONCLUSION: Chikungunya arthritis is characterized by increased inflammatory cytokines and deficient IL-2 and Treg responses. Greater levels of IL-2 were associated with improved Treg numbers and immunosuppressive markers. Future research may consider targeting these pathways for therapy.

Myocarditis after trimethoprim/sulfamethoxazole treatment for ehrlichiosis.

The manifestations of human monocytic ehrlichiosis range from a mild febrile syndrome to a severe multisystem illness. Myocardial involvement is uncommon. We report a woman, 78 years of age, who was treated with trimethoprim/sulfamethoxazole after a tick bite, in whom myocarditis was subsequently diagnosed. She recovered completely after doxycycline therapy.

Effects of IL2/anti-IL2 antibody complex on chikungunya virus-induced arthritis in a mouse model.

Chikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arthritis in approximately one-fourth of patients. Currently, no standard treatments are available for chronic CHIKV arthritis. Our preliminary data suggest that decreases in interleukin-2 (IL2) levels and regulatory T cell (Treg) function may play a role in CHIKV arthritis pathogenesis. Low-dose IL2-based therapies for autoimmune diseases have been shown to up-regulate Tregs, and complexing IL2 with anti-IL2 antibodies can prolong the half-life of IL2. A mouse model for post-CHIKV arthritis was used to test the effects of IL-2, an anti-IL2 monoclonal antibody (mAb), and the complex on tarsal joint inflammation, peripheral IL2 levels, Tregs, effector (Teff) T cells, and histological disease scoring. The complex treatment resulted in the highest levels of IL2 and Tregs, but also increased Teffs, and therefore did not significantly reduce inflammation or disease scores. However, the antibody group, which had moderately increased levels of IL2 and activated Tregs, resulted in a decreased average disease score. These results suggest the IL2/anti-IL2 complex stimulates both Tregs and Teffs in post-CHIKV arthritis, while the anti-IL2 mAb increases IL2 availability enough to shift the immune environment towards a tolerogenic one.

Effects of rIL2/anti-IL2 antibody complex on chikungunya virus-induced chronic arthritis in a mouse model.

Chikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arthritis in approximately one-fourth of patients. Currently, no standard treatments are available for chronic CHIKV arthritis. Our preliminary data suggest that decreases in interleukin-2 (IL2) levels and regulatory T cell (Treg) function may play a role in CHIKV arthritis pathogenesis. Low-dose IL2-based therapies for autoimmune diseases have been shown to up-regulate Tregs, and complexing IL2 with anti-IL2 antibodies can prolong the half-life of IL2. A mouse model for post-CHIKV arthritis was used to test the effects of recombinant IL2 (rIL2), an anti-IL2 monoclonal antibody (mAb), and the complex on tarsal joint inflammation, peripheral IL2 levels, Tregs, CD4 + effector T cells (Teff), and histological disease scoring. The complex treatment resulted in the highest levels of IL2 and Tregs, but also increased Teffs, and therefore did not significantly reduce inflammation or disease scores. However, the antibody group, which had moderately increased levels of IL2 and activated Tregs, resulted in a decreased average disease score. These results suggest the rIL2/anti-IL2 complex stimulates both Tregs and Teffs in post-CHIKV arthritis, while the anti-IL2 mAb increases IL2 availability enough to shift the immune environment towards a tolerogenic one.

Cardiovascular disease (CVD) risk assessment of HIV medication regimens using hematopoietic CD34+ progenitor cells.

BACKGROUND: To determine the effects of integrase inhibitor (INSTI) in comparison with non-INSTI-based regimens such as non-nucleoside reverse transcriptase inhibitors (NNRTIs)-based regimens on cardiovascular disease (CVD) risk in HIV+ patients without overt history of CVD or diabetes, with normal CD4:CD8 count. For CVD risk assessment we primarily used hematopoietic CD34+ progenitor cells, as a biomarker. METHODS: Nineteen male subjects, ages 32-61 years with BMI 21.0-36.0, were enrolled. This was a single time point, cross-sectional, observational study. Subjects were enrolled under 2 groups (either on INSTI-based regimen with 13 subjects or NNRTI (non-INSTI)-based regimens with 6 subjects) who were taking stable doses of HAART. The medication regimens were a combination of one NRTI (typically tenofovir-emtricitabine) plus one INSTI or NNRTI. Our outcome measures were focused on cardiovascular and endothelial cell function and systemic inflammation. Our primary outcome measures were peripheral blood-derived hematopoietic progenitor cell number (CD34 and CD133 positive), CD34+ cell function and gene expression studies. Our secondary outcomes were arterial stiffness measures and serum-based markers of inflammation. RESULTS: A significant increase in percentage number of progenitor cells, CD133+ cells (p = 0.004), was noted along with an increase of double progenitor mark positive CD133+/CD34+ progenitor cell population being observed in INSTI group as compared to NNRTI group, by flow cytometry. mRNA gene expression for antioxidant gene catalase was noted along with a trend toward a decrease in gene expression of inflammatory marker IL6 (p = 0.06) being observed in CD34+ from INSTI group vs NNRTI group. The plasma IL-6 and CRP levels did not change significantly between the groups. Neutrophil-Lymphocyte ratio (NLR), an important marker of inflammation, was noted to be lower in INSTI group. A mean fasting glucose level was also lower in the INSTI group compared to NNRTI group (p = 0.03). Interestingly, urine microalbumin levels were higher in the INSTI group compared to NNRTI group (p = 0.08), while eGFR levels were significantly lower in the INSTI group (p = 0.002). The arterial stiffness measures did not show statistically significant differences between the two groups. CONCLUSION: We conclude that the INSTI regimen may provide a better CVD risk profile compared to NNRTI-based HAART regimen; however, the increased albuminuria along with lower eGFR, noted in INSTI group, is of concern. Because of the small size, these results would need replication in additional studies before changing clinical practice. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT03782142?cond=Hiv&spons=Sabyasachi+sen&cntry=US&state=US%3ADC&city=Washington&draw=2&rank=1 . CLINICALTRIALS: gov Identifier: NCT03782142.

Ureaplasma septic polyarthritis in a young woman with neuromyelitis optica receiving rituximab.

We report a case of septic polyarthritis caused by Ureaplasma urealyticum in a woman with neuromyelitis optica who was receiving rituximab. Her case exemplifies some of the unique characteristics of invasive Ureaplasma infections that can lead to delayed diagnosis as well as treatment challenges including recurrence following antibiotic discontinuation.

A Mouse Model for Studying Post-Acute Arthritis of Chikungunya.

Chikungunya virus (CHIKV) was introduced to the Americas in 2013, causing two million infections across over thirty countries. CHIKV causes a chronic debilitating arthritis in one fourth of infected individuals and currently evidence-based targeted therapies for the treatment of CHIKV arthritis are lacking. Multiple mouse models of chikungunya have been developed to study acute CHIKV infection. In humans, post-CHIKV arthritis may persist for months to years after viremia from a CHIKV infection has resolved. Therefore, the development of a mouse model of post-acute arthritis of chikungunya may facilitate the study of potential novel therapeutics for this arthritis. In this article we describe the development of a wild-type immunocompetent C57BL/6 mouse model for post-acute arthritis of chikungunya, including a histologic inflammation scoring system, as well as suggestions for how this mouse model may be used to examine the efficacy of novel therapies for CHIKV arthritis.

Atrial-esophageal fistula after atrial radiofrequency catheter ablation.

Atrial-esophageal fistula is a rare but often fatal complication of catheter radiofrequency ablation. Patients occasionally have bacteremia and have been misdiagnosed with endocarditis. Infectious diseases specialists are often consulted and need to be aware of this complication. We report a case of atrial-esophageal fistula after radiofrequency ablation that illustrates the salient features of this illness.

Characteristics and Severity of Disease among 100 Cases of Imported Malaria Seen at a U.S. University Hospital, 2000-2017.

Malaria acquired in endemic areas poses a substantial risk to travelers arriving in or returning to the United States. Timely diagnosis and recognition of severe illness are crucial; however, many U.S.-based clinicians lack familiarity with this disease. We conducted a retrospective review of 100 cases of malaria in adults seen at a single urban university hospital during 2000-2017. Descriptive and analytical statistics were calculated, including logistic regression modeling case severity. Most of the patients presented with Plasmodium falciparum (76%), most commonly after travel from sub-Saharan Africa (94%). Prior malaria experience was common (50%), but adherence to a prophylactic regimen was exceedingly rare (4%). Twenty-one patients had severe malaria, including 10 with cerebral malaria. Severity was predicted by high parasitemia, bandemia, hypoglycemia, and hypotension at the time of presentation. In 24 patients, the initial treatment regimen was changed, usually because of the appearance of clinical deterioration or drug toxicity. One patient required intravenous artesunate. All patients survived, although one suffered fetal loss. Among 30 patients initially evaluated at other institutions, 43% had been treated for an alternative diagnosis. The most common reasons for transfer of patients to our hospital were inadequate facilities and lack of expertise with malaria. There needs to be increased awareness among U.S.-based travelers and clinicians regarding malaria as a potentially lethal condition, emphasizing the use of appropriate prophylaxis. Our simple model of disease severity could serve frontline physicians when deciding which patients should be admitted to the intensive care unit or transferred for higher level care.

Second-trimester Ultrasound and Neuropathologic Findings in Congenital Zika Virus Infection.

Zika virus is a mosquito-borne virus that causes congenital Zika syndrome, characterized by microcephaly and other fetal brain anomalies. This case report presents a case of Zika virus-related fetal brain anomalies including pathologic evidence of cerebral neuronal apoptosis and macrophage infiltrates and intracerebral calcification, ventriculomegaly and corpus callosum dysgenesis detected by ultrasound at 18 weeks of pregnancy.

The Cytokine Profile in Acute Chikungunya Infection is Predictive of Chronic Arthritis 20 Months Post Infection.

The cytokine profile during acute chikungunya infection that predicts future chronic arthritis has not yet been investigated. We conducted a nested case-control study comparing serum cytokine concentrations during acute chikungunya infection in cases (n = 121) that reported the presence of chronic joint pain versus age- and gender-matched controls (n = 121) who reported recovery at 20 months post infection. We observed that a robust cytokine response during acute infection was correlated with a decreased incidence of chronic joint pain and that low TNFα, IL-13, IL-2, and IL-4 during acute infection was predictive of chronic joint pain. These data suggest that a robust cytokine response is necessary for viral clearance and cytokines that are related to immune tolerance during acute infection may be protective for chronic arthritis pathogenesis.

Frequency of Chronic Joint Pain Following Chikungunya Virus Infection: A Colombian Cohort Study.

OBJECTIVE: To estimate the frequency of chronic joint pain after infection with chikungunya virus in a Latin American cohort. METHODS: A cross-sectional follow-up of a prospective cohort of 500 patients from the Atlántico Department, Colombia who were clinically diagnosed as having chikungunya virus during the 2014-2015 epidemic was conducted. Baseline symptoms and follow-up symptoms at 20 months were evaluated in serologically confirmed cases. RESULTS: Among the 500 patients enrolled, 485 had serologically confirmed chikungunya virus and reported joint pain status. Patients were predominantly adults (mean ± SD age 49 ± 16 years) and female, had an education level of high school or less, and were of Mestizo ethnicity. The most commonly affected joints were the small joints, including the wrists, ankles, and fingers. The initial virus symptoms lasted a median of 4 days (interquartile range [IQR] 3-8 days). Sixteen percent of the participants reported missing school or work (median 4 days [IQR 2-7 days]). After 20 months, one-fourth of the participants had persistent joint pain. A multivariable analysis indicated that significant predictors of persistent joint pain included college graduate status, initial symptoms of headache or knee pain, missed work, normal activities affected, ≥4 days of initial symptoms, and ≥4 weeks of initial joint pain. CONCLUSION: This is the first report to describe the frequency of chikungunya virus-related arthritis in the Americas after a 20-month follow-up. The high frequency of chronic disease highlights the need for the development of prevention and treatment methods.