United States Regulatory Approval of Topical Treatments for Dry Eye.

PURPOSE: To report the heterogeneity in methodology of clinical trials submitted to the US Food and Drug Administration (FDA) for approval of topical dry eye treatments. DESIGN: Comparative analysis of clinical trials' methods. METHODS: We reviewed the online, publicly available FDA database, application review files, ClinicalTrials.gov registry records, and journal articles for each FDA-approved topical dry eye treatment. For each trial, we extracted information about the study, patient demographics, treatment names and doses, sample size in each arm, and the measurement instrument in a systematic fashion. RESULTS: Fourteen trials were included that assessed 5 topical treatments for dry eye (cyclosporine 0.05%, cyclosporine 0.09%, lifitegrast 5%, and loteprednol 0.25% eye drops and varenicline 0.03-mg nasal spray). Median treatment duration was 12 weeks (range, 2-24 weeks). In all trials, treatments, including varying concentrations of the same treatment, were compared with vehicle. Twelve trials (85.7%) evaluated a primary clinician-measured clinical sign, and 10 trials (71.4%) evaluated a primary patient-reported symptom. Corneal staining was the most frequently evaluated clinical sign primary outcome, reported in half (6 of 12) of the trials, and was graded using 4 different scoring systems. Conjunctival staining, conjunctival hyperemia, and tear production were each measured using 2 different scoring systems. Ocular discomfort, the only patient-reported symptom primary outcome, was measured using 5 different instruments. CONCLUSION: A variety of outcome measures were used in these clinical trials. Clinically meaningful dry eye outcome measures and standardized measurements can optimize the assessment of and comparison of therapeutic benefits.

Usability of Patient Education-Oriented Cataract Surgery Websites.

PURPOSE: To assess the web accessibility and readability of patient-oriented educational websites for cataract surgery. DESIGN: Cross-sectional electronic survey. PARTICIPANTS: Websites with information dedicated to educating patients about cataract surgery. METHODS: An incognito search for "cataract surgery" was performed using a popular search engine. The top 100 patient-oriented cataract surgery websites that came up were included and categorized as institutional, private practice, or medical organization according to authorship. Each site was assessed for readability using 4 standardized reading grade-level formulas. Accessibility was assessed through multilingual availability, accessibility menu availability, complementary educational video availability, and conformance and adherence to the Web Content Accessibility Guidelines (WCAG) 2.0. A standard t test and chi-square analysis were performed to assess the significance of differences with regard to readability and accessibility among the 3 authorship categories. MAIN OUTCOME MEASURES: The main outcome measures were the website's average reading grade level, number of accessibility violations, multilingual availability, accessibility menu availability, complementary educational video availability, accessibility conformance level, and violation of the perceivable, operable, understandable, and robust (POUR) principles according to the WCAG 2.0. RESULTS: A total of 32, 55, and 13 sites were affiliated with institutions, private practice, and other medical organizations, respectively. The overall mean reading grade was 11.8 ± 1.6, with higher reading levels observed in private practice websites compared with institutions and medical organizations combined (12.1 vs. 11.4; P = 0.03). Fewer private practice websites had multiple language options compared with institutional and medical organization websites combined (5.5% vs. 20.0%; P = 0.03). More private practice websites had accessibility menus than institutions and medical organizations combined (27.3% vs. 8.9%; P = 0.038). The overall mean number of WCAG 2.0 POUR principle violations was 17.1 ± 23.1 with no significant difference among groups. Eighty-five percent of websites violated the perceivable principle. CONCLUSIONS: Available patient-oriented online information for cataract surgery may not be comprehensible to the general public. Readability and accessibility aspects should be considered when designing these resources. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Impact of enhanced recovery pathways on patient-reported outcomes after abdominal surgery: a systematic review.

INTRODUCTION: Evidence supports that enhanced recovery pathways (ERPs) reduce length of stay and complications; however, these measures may not reflect the perspective of patients who are the main stakeholders in the recovery process. This systematic review aimed to appraise the evidence regarding the impact of ERPs on patient-reported outcomes (PROs) after abdominal surgery. METHODS: Five databases (Medline, Embase, Biosis, Cochrane, and Web of Science) were searched for randomized controlled trials (RCTs) addressing the impact of ERPs on PROs after abdominal surgery. We focused on distinct periods of recovery: early (within 7 days postoperatively) and late (beyond 7 days). Risk of bias was assessed using Cochrane's RoB 2.0. Results were appraised descriptively as heterogeneity hindered meta-analysis. Certainty of evidence was evaluated using GRADE. RESULTS: Fifty-six RCTs were identified [colorectal (n = 18), hepatopancreaticobiliary (HPB) (n = 11), upper gastrointestinal (UGI) (n = 10), gynecological (n = 7), urological (n = 7), general surgery (n = 3)]. Most trials had 'some concerns' (n = 30) or 'high' (n = 25) risk of bias. In the early postoperative period, ERPs improved patient-reported general health (colorectal, HPB, UGI, urological; very low to low certainty), physical health (colorectal, gynecological; very low to low certainty), mental health (colorectal, gynecological; very low certainty), pain (all specialties; very low to moderate certainty), and fatigue (colorectal; low certainty). In the late postoperative period, ERPs improved general health (HPB, UGI, urological; very low certainty), physical health (UGI, gynecological, urological; very low to low certainty), mental health (UGI, gynecological, urological; very low certainty), social health (gynecological; very low certainty), pain (gynecological, urological; very low certainty), and fatigue (gynecological; very low certainty). CONCLUSION: This review supports that ERPs may have a positive impact on patient-reported postoperative health status (i.e., general, physical, mental, and social health) and symptom experience (i.e., pain and fatigue) after abdominal surgery; however, data were largely derived from low-quality trials. Although these findings contribute important knowledge to inform evidence-based ERP implementation, there remains a great need to improve PRO assessment in studies focused on postoperative recovery.

Racial and Ethnic Disparities in Dry Eye Diagnosis and Care.

PURPOSE: To investigate health disparities in racial and ethnic minorities with dry eye. METHODS: Medical records were reviewed for demographics, socioeconomic factors, treatments, and objective dry eye parameters. Race/ethnicity was self-reported as delineated by the U.S. Census. The reference group comprised of randomly selected White patients, with number equal to the largest minority group. RESULTS: The study included 465 patients (157 Black, 157 White, 85 Asian, and 66 Hispanic). Compared to White (3.2%) patients, larger proportion of minorities used Medicaid or lacked health insurance (Black 8.3%, P = .054; Asian 10.6%, P = .019; Hispanic 18.2%, P < .001). Black and Hispanic patients had lower estimated median household income than Whites (White $98,472, Black $75,554, P < .001; Asian $105,503, P = .088; Hispanic $86,839, P = .030). Prior to presentation, fewer minority patients received prescription treatments or procedures (White 61.8%; Black 30.6%, P < .001; Asian 43.5%, P = .006; Hispanic 43.9%, P = .014). Although at baseline visit minorities had worse mean conjunctival (White, 1.7; Black 2.2, P = .136, Asian 2.4, P = .022; Hispanic 2.6, P = .005) and corneal staining scores (White, 1.6; Black 2.5, P < .001; Asian 2.3, P = .003; Hispanic 2.4, P = .001), no differences were noted at final visit. CONCLUSION: Minorities presented with worse objective dry eye parameters, and less prior dry eye care. Income and health care access may not fully explain the observed undertreatment at presentation. Differential management by eye care providers and patient attitudes warrant further investigation.

Association of staffing with Incidence of delayed retinal break or detachment after posterior vitreous detachment in a resident urgent care clinic.

PURPOSE: To compare the incidence rate of delayed retinal break or detachment after diagnosis of acute, symptomatic posterior vitreous detachment (PVD) in a resident-run urgent care clinic (UCC) when staffed by a retina attending, non-retina ophthalmology attending, optometrist, or ophthalmology resident only. METHODS: Retrospective consecutive case series. Of the 594 patients with acute, symptomatic PVD evaluated in the UCC at Penn State Eye Center between 1/1/2016 and 10/10/2019, 454 were included in the study; 140 were excluded because they were diagnosed with a retinal break or detachment on presentation to the UCC, had media opacity precluding examination, or had no follow-up within one year. Demographics, presenting examination findings, and type of staffing were recorded; subsequent visits up to 1 year were analyzed for presence of delayed retinal break or detachment. RESULTS: Among 491 eyes of 454 patients with a mean follow-up of 147 days, ten delayed breaks (10/491, 2.0%) and three delayed detachments (3/491, 0.6%) were discovered. Incidence rates of delayed breaks and detachments were 1.8% (5/282) and 0.7% (2/282), respectively, in the retina attending group, 1.0% (1/105) and 1.0% (1/105) in the non-retina ophthalmology attending group, 4.7% (3/64) and 0% (0/64) in the optometrist group, and 2.5% (1/40) and 0% (0/40) in the ophthalmology resident only group. There was no statistically significant difference in the incidence of delayed break or detachment among the staffing groups (P = 0.7312), but this study was underpowered to detect a statistically significant difference among staffing groups. Patients with a delayed break or detachment were more likely to have lattice degeneration (P = 0.0265) or a history of retinal break in the contralateral eye (P = 0.0014), and most eyes (10 [76.9%]) with a delayed break or detachment were left eyes (P = 0.0466). CONCLUSIONS: The overall rate of delayed retinal break or detachment in the current study is similar to previously published rates among retinal physician and retinal fellow examiners. Although no statistically significant difference among staffing groups in the incidence rates of delayed retinal tears or detachments was identified in the study, it is important to note that the optometry and ophthalmology resident only groups had higher incidence rates of delayed retinal breaks than did the retina and non-retina ophthalmology attending groups, and this may be clinically important. Larger cohort studies would be needed in order to have the power to detect statistically significant differences among staffing groups. Varied staffing for acute, symptomatic PVD may assist with resource allocation in similar settings.

Outcomes of Sjögren's versus non-Sjögren's related dry eye in a longitudinal, tertiary clinic-based sample.

PURPOSE: To assess the long-term treatment outcomes of dry eye in patients with and without underlying primary Sjögren's syndrome (SS). DESIGN: Retrospective longitudinal cohort. METHODS: SS and non-SS dry eye patients with clinic visits for a minimum of 5 consecutive years at a tertiary, dedicated dry eye clinic were included. Electronic health records were reviewed to collect data regarding demographics, objective dry eye parameters, treatments utilized at baseline and final visit, and corneal complications observed during follow-up. RESULTS: Two hundred and two patients (101 SS and 101 randomly selected non-SS), with a mean follow-up of 7.1 years were included. At baseline, mean conjunctival lissamine green staining score was 2.9 and mean corneal fluorescein staining score was 2.0. At last visit, notable improvement in staining score for cornea (-1.1, P < .001) and conjunctiva (-1.8, P < .001) was seen equally in both dry eye groups. Most patients (88.1%) had an escalation of treatment by the final visit, with similar rates in both groups (P = .51). Half (48.9%) of the patients had no conjunctival staining, and a third (34.4%) had no corneal staining at their last visit. Twenty (9.9%) patients experienced a vision-threatening corneal complication, including ulcers and melt, with no difference in occurrences between the groups (P = .64). CONCLUSIONS: The majority of patients in this longitudinal, tertiary clinic-based sample demonstrated improvement in their ocular surface staining score by the final visit with escalation in treatment. Treatments used, improvement achieved, and corneal complication rates leading to loss of vision were similar in both SS and non-SS dry eye groups.

Autologous serum eye drops for ocular surface disorders.

PURPOSE OF REVIEW: Ocular surface disease is a prevalent, diverse group of conditions that cause patient discomfort and decreased visual acuity and present considerable expense to both patients and healthcare systems. Autologous serum eye drops are a topical treatment modality derived from the patient's own blood. Use of serum eye drops for ocular surface disease has been promising due to biochemical similarities to endogenous tears. RECENT FINDINGS: Use of serum eye drops for moderate to severe ocular surface diseases such as dry eye, corneal epithelial defects, and inflammatory conditions has become more prevalent. Recent studies have demonstrated that the use of serum eye drops is well-tolerated by patients and associated with improvement in patient-reported outcomes and objective dry eye parameters. Production of serum eye drops may vary, treatment costs can be significant, and the quality of evidence for serum eye drop use published from randomized controlled trials is modest, particularly for long-term treatment. Accessibility remains an area for improvement and may be complemented by allogeneic serum eye drops. SUMMARY: Serum eye drops are frequently used as a safe, well-tolerated, and effective treatment for ocular surface disease. Further research is needed to assess long-term outcomes and improve accessibility.

A comparison of orthopaedic surgery and internal medicine perceptions of USMLE Step 1 pass/fail scoring.

BACKGROUND: United States Medical Licensing Examination Step 1 will transition from numeric grading to pass/fail, sometime after January 2022. The aim of this study was to compare how program directors in orthopaedics and internal medicine perceive a pass/fail Step 1 will impact the residency application process. METHODS: A 27-item survey was distributed through REDCap to 161 U.S. orthopaedic residency program directors and 548 U.S. internal medicine residency program directors. Program director emails were obtained from the American Medical Association's Fellowship and Residency Electronic Interactive Database. RESULTS: We received 58 (36.0%) orthopaedic and 125 (22.8%) internal medicine program director responses. The majority of both groups disagree with the change to pass/fail, and felt that the decision was not transparent. Both groups believe that the Step 2 Clinical Knowledge exam and clerkship grades will take on more importance. Compared to internal medicine PDs, orthopaedic PDs were significantly more likely to emphasize research, letters of recommendation from known faculty, Alpha Omega Alpha membership, leadership/extracurricular activities, audition elective rotations, and personal knowledge of the applicant. Both groups believe that allopathic students from less prestigious medical schools, osteopathic students, and international medical graduates will be disadvantaged. Orthopaedic and internal medicine program directors agree that medical schools should adopt a graded pre-clinical curriculum, and that there should be a cap on the number of residency applications a student can submit. CONCLUSION: Orthopaedic and internal medicine program directors disagree with the change of Step 1 to pass/fail. They also believe that this transition will make the match process more difficult, and disadvantage students from less highly-regarded medical schools. Both groups will rely more heavily on the Step 2 clinical knowledge exam score, but orthopaedics will place more importance on research, letters of recommendation, Alpha Omega Alpha membership, leadership/extracurricular activities, personal knowledge of the applicant, and audition electives.

Cicatrizing conjunctivitis as an uncommon manifestation of primary Sjögren's syndrome.

PURPOSE: To report occurrence of cicatrizing conjunctivitis as an extraglandular ocular manifestation of primary Sjögren's syndrome (SS). METHODS: Medical charts of all patients with SS evaluated at two tertiary ophthalmological referral centers were reviewed. Patients who demonstrated clinical findings of cicatrizing conjunctivitis were included in this review. Patient and disease-related data including ocular complications, therapies and outcomes were collected. RESULTS: Eight patients with a diagnosisis of SS were noted to have cicatrizing conjunctivitis findings over a period of 11 years (between 2009 and 2020). Mean age of patients was 79. All patients had a negative immunoreactant deposition in conjunctival biopsy. Mean follow-up time was 6 years (range, 18-197 months). Three patients had progression of conjunctival scarring. Worsening of vision occurred in 4 patients due to corneal complications, including ulceration, perforation and scarring. CONCLUSIONS: SS is an under-recognized etiology of severe progressive cicatrizing conjunctivitis that can lead to ocular morbidity and loss of vision without appropriate management.

Factors Influencing Choice of Medical Specialty among Ophthalmology and Non-Ophthalmology Residency Applicants.

Objective The study aimed to investigate factors influencing choice of specialty among ophthalmology and non-ophthalmology residency applicants. Patients and Methods Anonymous, web-based surveys were distributed through REDCap to the 2019 to 2020 residency applicants to the Penn State Department of Ophthalmology and, as a control group, Penn State medical students applying to non-ophthalmology residencies for the 2019 to 2020 cycle. The primary outcome was factors that influenced specialty choice among ophthalmology versus non-ophthalmology applicants. Secondary outcomes include hours of exposure to applicants' selected specialty in the medical school preclinical curriculum, and proportion of ophthalmology versus non-ophthalmology applicants who decided on, or developed a strong interest in, their specialty prior to clinical rotations. Results Surveys were completed by 203/441 (46.0%) ophthalmology and 85/139 (61.1%) non-ophthalmology applicants. Fewer than 20 hours of exposure to an applicant's selected specialty were provided in the medical school preclinical curriculum for 86.7% of ophthalmology and 42.4% of non-ophthalmology applicants ( p < 0.001). Ophthalmology applicants decided on, or developed a strong interest in, their selected specialty before clinical rotations at a similar rate to non-ophthalmology applicants (60.6 vs. 58.8%, respectively). Factors influencing specialty choice cited most commonly by ophthalmology applicants include professional satisfaction (94.1%), performing surgeries/procedures (92.6%), personal fit with specialty (91.1%), work-life balance (91.1%), and ability to see patients in a clinic setting (90.6%), compared to personal fit with specialty (95.3%)%, clinical rotation in selected specialty (95.3%), professional satisfaction (91.8%), intellectual stimulation (89.4%), and subinternship or away rotation (89.4%) among non-ophthalmology applicants. Conclusion Professional satisfaction and personal fit with specialty were among the most commonly cited factors influencing specialty choice for both groups. Other factors cited most frequently by ophthalmology applicants include performing surgeries/procedures, work-life balance, and ability to see patients in a clinic setting. Despite limited ophthalmology exposure in medical school preclinical curricula, ophthalmology applicants decided on, or developed a strong interest in, their selected specialty before clinical rotations at a rate similar to non-ophthalmology applicants.

Anterior, posterior, and nonkeratometric contributions to refractive astigmatism in pseudophakes.

PURPOSE: To investigate the relationship between measured anterior (ACA) and posterior (PCA) keratometric astigmatism and postoperative refractive astigmatism (RA) and to quantify noncorneal astigmatism (NCA) contributions to RA. SETTING: Penn State College of Medicine, Hershey, Pennsylvania, USA. DESIGN: Retrospective consecutive case series. METHODS: Consecutive eyes underwent preoperative biometry (IOLMaster 700) and tomography/topography using a dual Scheimpflug-placido disk-based device (Galilei G4), cataract surgery with implantation of a monofocal intraocular lens (IOL), and postoperative manifest refractions. RA was compared with keratometric astigmatism using the following methods: IOLMaster, SimK, CorT, SimK + measured PCA, total corneal power at the corneal plane (TCP2), and CorT(Total). An ocular residual astigmatism (ORA) vector was calculated between RA and each measured astigmatism. RESULTS: Analysis was based on 296 eyes. ORA centroids were 0.28 @ 179, 0.45 @ 001, 0.37 @ 001, 0.19 @ 003, 0.19 @ 001, and 0.23 @ 178 diopter (D) for the 6 aforementioned methods, respectively (P < .000001 [ORAx, ORAy]). Based on TCP2 measurements, eyes with against-the-rule ACA and with-the-rule (WTR) ACA had ORA centroids of 0.09 @ 082 and 0.58 @ 001 D (P < .000001 [ORAx, ORAy]), respectively. ORA was nonzero and not entirely explained by the cornea, especially in those with WTR ACA. CONCLUSIONS: Total keratometric astigmatism did not explain all ocular astigmatism. Noncorneal contributions were significant, especially in eyes with WTR ACA.

Repeatability and comparability of keratometry measurements obtained with swept-source optical coherence and combined dual Scheimpflug-Placido disk-based tomography.

PURPOSE: To assess the repeatability of keratometric measurements obtained using a reflectance and swept-source optical coherence tomography (SS-OCT) based biometer and to compare these values with those obtained with a dual Scheimpflug-Placido (S-P) disk-based tomographer/topographer. SETTING: Department of Ophthalmology, Penn State College of Medicine, Hershey, Pennsylvania, USA. DESIGN: Prospective consecutive case series. METHODS: Patients undergoing cataract evaluation were prospectively enrolled. Surgery-naive eyes without corneal pathology were measured 3 times with the reflectance/SS-OCT biometer and once with the dual S-P disk tomographer/topographer. Intradevice repeatability for anterior (K), posterior (PK), and total corneal keratometry (TK) readings were evaluated using within-eye SDs, test-retest repeatability (TRT), coefficients of variance, and intraclass correlation coefficients (ICCs). Bland-Altman analysis was used to assess agreement between devices. RESULTS: Eighty-two eyes from 48 patients met inclusion criteria. The TRT for the anterior, posterior, and total corneal powers were 0.33, 0.08, and 0.36 diopter (D), respectively. TRT for the anterior, posterior, and total keratometric astigmatism were 0.58, 0.14, and 0.64 D, respectively. Anterior keratometric indices had higher ICCs than posterior indices. Bland-Altman analysis revealed that the SS-OCT consistently reported flatter posterior corneal curvatures than the S-P. CONCLUSIONS: The SS-OCT posterior keratometric measurements contain more noise (lower ICCs), but still have lower within-eye SDs and TRTs than that of anterior measurements. This may be due to the small index of refraction change at the cornea-aqueous interface. Although keratometric indices from the 2 devices are highly correlated, measurements taken using SS-OCT and S-P devices were not interchangeable.

Concurrent primary Sjögren's syndrome and isolated ocular sarcoidosis presenting with bilateral corneal scarring and dry eye.

PURPOSE: To report the case of a patient who presents with multiple progressive ocular diseases who is diagnosed with concurrent primary Sjögren's syndrome and isolated ocular sarcoidosis. OBSERVATION: A 60-year-old woman was referred for dry eye disease, bilateral interstitial keratitis, anterior uveitis, and progressive glaucoma. There was clinical suspicion of an autoimmune etiology due to her ocular history, risk factors, and presentation. Thorough diagnostic testing revealed both primary Sjögren's syndrome and ocular sarcoidosis. After 2.5 years of systemic treatment and follow up, the patient currently remains stable. CONCLUSIONS AND IMPORTANCE: Autoimmune disease may underlie those with progressive ocular disease with an unknown etiology. More than one autoimmune disease may be the cause of ocular findings, especially for patients with a complicated presentation. Proper awareness, clinical suspicion, and diagnosis of these diseases can greatly improve a patient's condition and prevent future ocular and systemic complications.

Evolution of Workforce Diversity in Surgery✰.

OBJECTIVE: Assessing workforce diversity over time is essential to understanding how it has evolved and anticipating its future. We conducted the current study to evaluate gender, racial/ethnic, and duty trends over the past decade in general surgery and surgical subspecialties. DESIGN: This is a cross-sectional study. We calculated ratios and relative changes to assess potential differences of physicians' characteristics across time and surgical subspecialties. SETTING: We evaluated data acquired by the Association of American Medical Colleges. PARTICIPANTS: We extracted data from the 2000 to 2013 including the overall number of surgeons, surgeon race/ethnicity, gender, and primary professional activity. RESULTS: During 2000 to 2013, the total number of surgeons increased 11.5%, reaching 172,062 active surgeons and residents, the majority of whom were White (64%) or male (75%). However, from 2000 to 2013, most specialties showed some improvement in terms of including minorities and females. Most surgeons (98%) participate in patient care while a small portion are devoted to other activities (e.g., administrative, research, teaching; 2%). Both groups increased over the study period. CONCLUSIONS: Our findings suggest that the face of surgery is changing. Continuous monitoring of the surgical workforce is important to anticipate future needs and to serve a diverse patient population.

Detection of a novel avian influenza A (H7N9) virus in humans by multiplex one-step real-time RT-PCR assay.

BACKGROUND: A novel avian influenza A (H7N9) virus emerged in eastern China in February 2013. 413 confirmed human cases, including 157 deaths, have been recorded as of July 31, 2014. METHODS: Clinical specimens, including throat swabs, sputum or tracheal aspirates, etc., were obtained from patients exhibiting influenza-like illness (ILIs), especially from those having pneumonia and a history of occupational exposure to poultry and wild birds. RNA was extracted from these samples and a multiplex one-step real-time RT-PCR assay was developed to specifically detect the influenza A virus (FluA). PCR primers targeted the conserved M and Rnase P (RP) genes, as well as the hemagglutinin and neuraminidase genes of the H7N9 virus. RESULTS: The multiplex assay specifically detected the avian H7N9 virus, and no cross-reaction with other common respiratory pathogens was observed. The detection limit of the assay was approximately 0.05 50% tissue culture infective doses (TCID50), or 100 copies per reaction. Positive detection of the H7N9 virus in sputum/tracheal aspirates was higher than in throat swabs during the surveillance of patients with ILIs. Additionally, detection of the matrix (M) and Rnase P genes aided in the determination of the novel avian H7N9 virus and ensured the quality of the clinical samples. CONCLUSIONS: These results demonstrate that the multiplex assay detected the novel avian H7N9 virus with high specificity and sensitivity, which is essential for the early diagnosis and treatment of infected patients.

Increased frequency of circulating follicular helper T cells in children with hand, foot, and mouth disease caused by enterovirus 71 infection.

Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease (HFMD) in children. The role of T follicular helper (TFH) cells in EV71-infected children remains unclear in regulating humoral immunity. The frequency of circulating ICOS(high)/PD-1(high)CXCR5(+)CD4(+) TFH cells in the children with mild and severe EV71 infection and healthy controls (HC) was detected by flow cytometry, respectively. IL-21 and IL-6 mRNA expression and their serum levels, Bcl-6 mRNA expression, and specific neutralizing antibodies against EV71 (NAb-EV71) were measured. In the acute stage of patients with EV71 infection, increased frequencies of circulating TFH cells with ICOS(high) and PD-1(high) expression in the mild and severe patients were observed, and the positive correlations among the frequencies of circulating TFH cells and the serum levels of IL-21, IL-6, and NAb-EV71 titres were detected, respectively. Moreover, the expressions of IL-6 and IL-21 mRNA in PBMCs from patients were also significantly higher than those of HC. However, further analysis did not reveal any significant differences between mild and severe patients. These data indicate a role of TFH cells and associated cytokines in modulating the humoral response during the pathogenesis of EV71 infection.