Graft-vs-Host Disease

The participants in the SICCA cohort have been enrolled since 2004 at five collaborating academically-based research groups, located in Argentina, China, Denmark, Japan and the United States, and directed from the University of California, San Francisco (12 (link)) (Table 1). Subsequently, additional research groups joined the SICCA project: in 2007, from the United Kingdom and in 2009, from India and two additional sites in the United States.
To be eligible for the SICCA registry, participants must be at least 21 years of age and have at least one of the following: symptoms of dry eyes or dry mouth; a previous suspicion or diagnosis of SS; elevated serum antinuclear antibodies (ANA), positive rheumatoid factor (RF), or anti-SSA/B; bilateral parotid enlargement in a clinical setting of SS; a recent increase in dental caries; or have diagnoses of rheumatoid arthritis or systemic lupus erythematosus and any of the above. The rationale for these eligibility criteria is that only patients with such characteristics would be evaluated for SS or considered for enrollment in a clinical trial designed to evaluate a potential therapeutic agent for SS. Therefore our classification criteria target individuals with signs and symptoms that may be suggestive of SS, not the general population.
Participants are recruited through local or national SS patient support groups, healthcare providers, public media, and populations served by all nine SICCA research groups. Exclusion criteria include known diagnoses of: hepatitis C, HIV, sarcoidosis, amyloidosis, active tuberculosis, graft versus host disease, autoimmune connective tissue diseases other than rheumatoid arthritis or lupus; past head and neck radiation treatment; current treatment with daily eye drops for glaucoma; corneal surgery in the last 5 years to correct vision; cosmetic eyelid surgery in the last 5 years; or physical or mental condition interfering with successful participation in the study. Contact lens wearers are asked to discontinue wear for 7 days before the SICCA examination. We do not exclude participants taking prescription drugs that may affect salivary or lacrimal secretion, but record their use and all other medications currently taken.

From January 1, 2010, to June 30, 2012, adults 18 years of age or older were enrolled at three hospitals in Chicago (John H. Stroger, Jr., Hospital of Cook County, Northwestern Memorial Hospital, and Rush University Medical Center) and at two in Nashville (University of Tennessee Health Science Center–Saint Thomas Health and Vanderbilt University Medical Center). We sought to enroll all eligible adults; therefore, trained staff screened adults for enrollment at least 18 hours per day, 7 days per week. Written informed consent was obtained from all the patients or their caregivers before enrollment. The study protocol was approved by the institutional review board at each participating institution and at the CDC. Weekly teleconferences, enrollment reports, data audits, and annual study-site visits were conducted to ensure uniform procedures among the study sites. Patients or their caregivers provided demographic and epidemiologic data, and medical charts were abstracted for clinical data. All the authors vouch for the accuracy and completeness of the data and analyses reported and for the fidelity of the study to the protocol. All the authors made the decision to submit the manuscript for publication.
Adults were eligible for enrollment if they were admitted to a study hospital on the basis of a clinical assessment by the treating clinician; resided in the study catchment area (see the Supplementary Appendix, available with the full text of this article at NEJM.org); had evidence of acute infection, defined as reported fever or chills, documented fever or hypothermia, leukocytosis or leukopenia, or new altered mental status; had evidence of an acute respiratory illness, defined as new cough or sputum production, chest pain, dyspnea, tachypnea, abnormal lung examination, or respiratory failure; and had evidence consistent with pneumonia as assessed by means of chest radiography by the clinical team within 48 hours before or after admission.
Patients were excluded if they had been hospitalized recently (<28 days for immunocompetent patients and <90 days for immunosuppressed patients), had been enrolled in the EPIC study within the previous 28 days, were functionally dependent nursing home residents,^{14 (link)} or had a clear alternative diagnosis (see the Supplementary Appendix). Patients were also excluded if they had undergone tracheotomy, if they had a percutaneous endoscopic gastrostomy tube, if they had cystic fibrosis, if they had cancer with neutropenia, if they had received a solid-organ or hematopoietic stem-cell transplant within the previous 90 days, if they had active graft-versus-host disease or bronchiolitis obliterans, or if they had human immunodeficiency virus infection with a CD4 cell count of less than 200 per cubic millimeter.^{10 (link)}

Patients with normal eyelid and corneal anatomy were prospectively recruited from the Miami Veterans Affairs (VA) Healthcare System eye clinic between October 2013 and October 2017. Patients with scheduled appointments for regular check-ups, for new symptoms related to the eye, or for follow-up appointments, regardless of DE diagnosis, were included as potential participants.
Patients were excluded from participation if they had risk factors accounting for their dry eye symptoms, including: contact lens use, use of ocular medications other than artificial tears, history of refractive surgery, HIV, sarcoidosis, graft-versus host disease or a collagen vascular disease, presence of an active external ocular process, cataract surgery within the last 6 months, history of any glaucoma, or retinal surgery. Participants who did not speak and understand English well were also excluded. Informed consent was obtained from all subjects. Miami VA Institution Review Board approval was obtained to allow the prospective evaluation of subjects. The study was conducted in accordance to the principles of the Declaration of Helsinki and complied with the requirements of the United States Health Insurance Portability and Accountability Act.
In the original NPSI validation paper [8 (link)], the authors included only individuals with at least moderate levels of pain severity (visual analogue scale scores of ≥ 30mm out of 100mm), and for whom pain was due to peripheral or central nervous system injury as indicated by clinical history, laboratory data, and/or imaging. For ocular pain, there is currently no gold standard method to diagnose neuropathic ocular pain nor to verify ocular nervous system lesion. As such, in this paper, we took an inclusive approach, in order to provide a wide range of NPSI scores, and analyzed data from all individuals with reported eye pain, defined as a Numerical Rating Scale (NRS) score of ≥ 1 for average eye pain intensity during the past week.