Tuberculosis Disease Among Nonimmigrant Visa Holders Reported to US Quarantine Stations, January 2011-June 2016.

US-bound immigrants and refugees undergo a mandatory overseas medical examination that includes tuberculosis screening; this exam is not routinely required for temporary visitors applying for non-immigrant visas (NIV) to visit, work, or study in the United States. US health departments and foreign ministries of health report tuberculosis cases in travelers to Centers for Disease Control and Prevention Quarantine Stations. We reviewed cases reported to this passive surveillance system from January 2011 to June 2016. Of 1252 cases of tuberculosis in travelers reported to CDC, 114 occurred in travelers with a long-term NIV. Of these, 83 (73%) were infectious; 18 (16%) with multidrug-resistant tuberculosis (MDR TB) and one with extensively drug-resistant tuberculosis (XDR TB). We found evidence that NIV holders are diagnosed with tuberculosis disease in the United States. Given that long-term NIV holders were over-represented in this data set, despite the small proportion (4%) of overall non-immigrant admissions they represent, expanding the US overseas migration health screening program to this population might be an efficient intervention to further reduce tuberculosis in the United States.

A rare case of congenital insensitivity to pain with anhidrosis.

A 22-month-old girl of consanguineous parents was admitted with a high-grade fever. She was found to have insensitivity to painful stimuli and an absence of perspiration. She also displayed self-mutilating behaviour and was insensitive to cold/hot water on her body. On examination, there was loss of the tip of the tongue, missing teeth, generalised xerosis, and several ulcers at sites of minor trauma. She also had dysplastic nails and digital ulcers. Sensory examination demonstrated a complete lack of awareness of pain and temperature, vibration and fine touch were intact and lacrimation was normal. Differential diagnoses of hereditary sensory and autonomic neuropathy (HSAN), Lesch-Nyhan syndrome, hypohidrotic ectodermal dysplasia and leprosy were considered. Results of routine blood investigations including serum uric acid were normal. On performing clinical exome sequencing, the diagnosis of congenital insensitivity to pain with anhidrosis (CIPA) of autosomal recessive inheritance was confirmed. A novel, predicted to be pathogenic variant detected at exon 16 of the NTRK1 gene resulting in congenital insensitivity to pain with anhidrosis is reported.Abbreviations: CIPA: congenital Insensitivity to pain with anhidrosis; HSAN: hereditary sensory and autonomic neuropathy; NGF: nerve growth factor; NTRK1: neurotrophic tyrosine kinase receptor 1 gene; TrKA: tropomyosin receptor kinase A.

Normative data for aquagenic wrinkling of palms in children 1-15 years of age: A cross-sectional study.

BACKGROUND: Aquagenic wrinkling of palms (AWP) is emerging as a screening test for cystic fibrosis (CF). There is lack of normative data for the same in our population. OBJECTIVES: To generate normative data for AWP in children 1-15 years of age and to describe the factors associated with it. METHODS: Children aged 1-15 years were enrolled after obtaining informed consent and assent of the parent and child based on age. Information regarding age, gender, anthropometry, indications for visiting hospital and drug intake were noted down. Wrinkling test was done using distilled water maintained in room temperature. Sweat chloride analysis was done using Nano duct sweat analysis system for children having AWP within 3 min. The mean/median time to wrinkle was noted and presented as centile curves after smoothing. RESULTS: The mean (SD) and median (interquartile range [IQR]) aquagenic wrinkling time in children 1-15 years of age was 4.88 (1.066) and 5 (4-5.75) minutes respectively. The mean (SD) and median (IQR) time for AWP was 4.78 (1.076) and 5 (4-5) minutes respectively for boys and 4.98 (1.048) and 5 (4-6) minutes, respectively for girls. The time taken to wrinkle was observed to increase with age. Males have earlier AWP than females. There was no association between AWP and anthropometry or sweat chloride levels. CONCLUSION: We have estimated the normative data for AWP in children 1-15 years of age which can be used for CF screening in children with typical clinical features from resource limited settings.

COVID-19 cases reported in Colorado following screening at selected US airports, January - July 2020.

OBJECTIVE: We sought to estimate the proportion of air travelers who may have been infected with SARS-CoV-2 upon arrival to Colorado by comparing data on Colorado residents screened upon entering the US to COVID-19 cases reported in the state. Data on Colorado's screened passengers arriving into the US between January 17 and July 30, 2020 were compared to Colorado's Electronic Disease Reporting System. We conducted a descriptive analysis of true matches, including age, gender, case status, symptom status, time from arrival to symptom onset (days), and time from arrival to specimen collection date (days). RESULTS: Fourteen confirmed COVID-19 cases in travelers who were diagnosed within 14 days after arriving in Colorado were matched to the 8,272 travelers who underwent screening at 15 designated airports with a recorded destination of Colorado, or 0.2%. Most (N = 13/14 or 93%) of these infected travelers arrived in Colorado in March 2020; 12 (86%) of them were symptomatic. Entry screening for COVID-19 and the sharing of traveler information with the Colorado Department of Public Health and Environment appeared to identify few cases early in the pandemic. Symptom-based entry screening and sharing of traveler information was minimally effective at decreasing travel-associated COVID-19 transmission.

Development of a new multiplex PCR to detect fecal coccidian parasite.

BACKGROUND: Cryptosporidium spp., Cystoisospora belli and Cyclospora cayetanensis are common intestinal coccidian parasites causing gastroenteritis. The clinical presentation caused by each parasite is indistinguishable from each other. Uniplex polymerase chain reaction (PCR) for these three groups of intestinal coccidian parasites was developed by us in our laboratory. Thereafter, we planned to develop a single-run multiplex polymerase chain reaction (mPCR) assay to detect Cryptosporidium spp., C. belli and C. cayetanensis simultaneously from a stool sample and described it here as coccidian mPCR. METHODS: New primers for C. belli and C. cayetanensis were designed and uniplex PCRs were standardized. The coccidian mPCR was standardized with known positive DNA control isolates. It was validated with 58 known positive and 58 known negative stool samples, which were previously identified by uniplex PCR. RESULTS: The coccidian mPCR was standardized with earlier primers designed by us for Cryptosporidium spp. and C. cayetanensis, and a newly designed primer for the internal transcribed spacer-1 (ITS-1) gene for C. belli. The coccidian mPCR was 92.1% sensitive for Cryptosporidium spp., and 100% sensitive for C. belli and C. cayetanensis each, when tested on 116 known samples. It was 100% specific for all intestinal coccidian parasites. Two representative PCR products of the newly designed ITS-1 primer for C. belli were sequenced and submitted to the GenBank, which best match with the sequences of C. belli. CONCLUSION: A highly sensitive, specific, cost-effective, indigenous, single-run coccidian mPCR has been developed, which can simultaneously detect Cryptosporidium spp., C. belli and C. cayetanensis.

Pyridoxine Therapy: Not Just the Dose, the Duration Matters Too.

Pyridoxine-dependent epilepsy (PDE) (OMIM 266100) is an autosomal recessive disorder of lysine metabolism secondary to antiquitin deficiency. The prototypical presentation is intractable neonatal seizures that do not respond to conventional antiseizure medication but are well controlled by pyridoxine supplementation. Atypical forms account for one-third of the PDE spectrum and may escape early diagnosis. The common atypical presentations include the prenatal onset of seizures, seizures onset as delayed as 3 years of age, autism, arrested hydrocephalus, and fetal ventriculomegaly. Herein, we describe a 9-month-old child with neonatal-onset refractory seizures who failed two short trials of pyridoxine therapy and was later diagnosed with PDE by molecular studies. Regardless of the therapeutic response, a prolonged course of pyridoxine therapy is justified to identify delayed responders in infants with drug-refractory epilepsy of no apparent etiology.

Intra-spinal abscess due to Bacteroides fragilis and Klebsiella pneumoniae co-infection in a child with spinal dysraphism.

Bacteroides fragilis (B. fragilis) is an uncommon cause of spinal abscess. We present a case of an 18-month-old child, with spinal dysraphism-Spina bifida occulta, who developed intra-spinal abscess infection with B. fragilis and Klebsiella pneumoniae. Magnetic resonance imaging (MRI) of the brain and spine showed multiple abscesses extending through the presacral fistula into the spinal cord. Patient was surgically treated along with administration of antimicrobial agents (ceftriaxone and metronidazole), resulting in an excellent clinical outcome.

Cross-sectional survey of SARS-CoV-2 testing at US airports and one health department's proactive management of travelers.

BACKGROUND: Many health departments and private enterprises began offering SARS-CoV-2 testing to travelers at US airports in 2020. Persons with positive SARS-CoV-2 test results who have planned upcoming travel may be subject to US federal public health travel restrictions. We assessed availability of testing for SARS-CoV-2 at major US airports. We then describe the management of cases and close contacts at Denver International Airport's testing site. METHODS: We selected 100 US airports. Online surveys were conducted during November-December 2020 and assessed availability of testing for air travelers, flight crew, and airport employees. Respondents included health department (HD) staff or airport directors. We analyzed testing data and management practices for persons who tested positive and their close contacts at one airport (Denver International) from 12/21/2020 to 3/31/2021. RESULTS: Among the 100 selected airports, we received information on 77 airports; 38 (49%) had a testing site and several more planned to offer one (N = 7; 9%). Most sites began testing in the fall of 2020. The most frequently offered tests were RT-PCR or other NAAT tests (N = 28). Denver International Airport offered voluntary SARS-CoV-2 testing. Fifty-four people had positive results among 5724 tests conducted from 12/21/2020 to 3/31/2021 for a total positivity of < 1%. Of these, 15 were travelers with imminent flights. The Denver HD issued an order requiring the testing site to immediately report cases and notify airlines to cancel upcoming flight itineraries for infected travelers and their traveling close contacts, minimizing the use of federal travel restrictions. CONCLUSIONS: As of December 2020, nearly half of surveyed US airports had SARS-CoV-2 testing sites. Such large-scale adoption of airport testing for a communicable disease is unprecedented and presents new challenges for travelers, airlines, airports, and public health authorities. This assessment was completed before the US and other countries began enforcing entry testing requirements; testing at airports will likely increase as travel demand returns and test requirements for travel evolve. Lessons from Denver demonstrate how HDs can play a key role in engaging airport testing sites to ensure people who test positive for SARS-CoV-2 immediately before travel do not travel on commercial aircraft.

Molecular detection of Cystoisospora belli by single-run polymerase chain reaction in stool samples.

INTRODUCTION: Cystoisospora belli (C. belli) is the only pathogenic species of the Cystoisospora genus responsible for severe diarrhea in immunocompromised patients. Most common microscopic method of diagnosis is less sensitive due to intermittent shedding of oocysts. We developed a new single-run polymerase chain reaction (PCR)-based diagnostic assay for C. belli. METHODS: A new single-run PCR-based diagnostic assay was standardized for the detection of C. belli. Diagnostic reproducibility and repeatability of the PCR assay were evaluated. A cross-sectional analytical study was done on a total of 354 stool samples collected from 331 immunocompromised patients with diarrhea. All the stool samples were tested for the presence of oocysts of C. belli and were also tested by our new PCR assay for C. belli. Three of the representative PCR products were confirmed by sequencing. Fisher's exact test was used to compare the two proportions. RESULTS: Microscopy detected C. belli in 11/354 (3.1%) of stool samples, and the new PCR-based assay detected C. belli in 16/354 (4.5%). The new single-run PCR-based assay detected C. belli in all the stool samples which were tested positive by microscopy and additionally detected C. belli in five stool samples. The developed PCR assay detected statistically significant proportion of C. belli (p < 0.001) as compared to microscopy. The 795 base pair PCR product from one microscopy positive stool sample and two microscopy negative stool samples were confirmed by sequencing. CONCLUSION: Our newly developed single-run PCR-based detection assay for C. belli is robust and reproducible. It may be used for molecular diagnosis of cystoisosporiasis especially in transplant, pediatrics, and human immunodeficiency virus (HIV) positive patients.

Clinical Characteristics, Molecular Profile, and Outcomes in Indian Patients with Glutaric Aciduria Type 1.

Glutaric acidemia type 1 (GA-1, OMIM 231670) is an autosomal recessive inborn error of metabolism caused by the deficiency of glutaryl-coenzyme A (CoA) dehydrogenase with most children presenting in infancy with encephalopathy, dystonia, and macrocephaly. In this article, we presented the clinical characteristics, molecular profile, and outcomes in 29 unrelated families with affected children (30 cases total). The mean age at onset of illness was 10 months (±14.58), whereas the mean age at referral for molecular diagnosis was 29.44 months (±28.11). Patients were residents of nine different states of India. Clinical presentation varied from acute encephalitis followed by neuroregression and chronic/insidious developmental delay. Neurological sequelae varied from asymptomatic (no sequelae, 2 patients) to moderate (5 patients) and severe (23 patients) sequelae. All patients underwent blood tandem mass spectrometry (TMS on dried blood spots) and/or urine gas chromatography mass spectrometry (GCMS). Neuroimaging demonstrated batwing appearance in 95% cases. Sanger's sequencing of GCDH , covering all exons and exon-intron boundaries, was performed for all patients. Variants identified include 15 novel coding variants: p.Met100Thr, p.Gly107Ser, p.Leu179Val, p.Pro217Ser, p. Phe236Leufs*107, p.Ser255Pro, p.Met266Leufs*2, p.Gln330Ter, p.Thr344Ile, p.Leu345Pro, p.Lys377Arg, p.Leu424Pro, p.Asn373Lys, p.Lys377Arg, p.Asn392Metfs*9, and nine known genetic variants such as p.Arg128Gln, p.Leu179Arg, p.Trp225Ter, p.Met339Val, p.Gly354Ser, p.Arg402Gln, p.Arg402Trp, p.His403Tyr, and p.Ala433Val (Ensembl transcript ID: ENST00000222214). Using in silico analysis, genetic variants were shown to be affecting the residues responsible for homotetramer formation of the glutaryl-CoA dehydrogenase protein. Treatment included oral carnitine, riboflavin, protein-restricted diet, lysine-deficient special formulae, and management of acute crises with intravenous glucose and hydration. However, the mortality (9/30, 27.58%) and morbidity was high in our cohort with only two patients affording the diet. Our study is the largest multicentric, genetic variant-proven series of glutaric aciduria type 1 from India till date.

Association of HLA-G, HLA-E and HLA-B*27 with susceptibility and clinical phenotype of enthesitis related arthritis (ERA).

We studied the association of Enthesitis related arthritis (ERA) the most common variant of juvenile idiopathic arthritis (JIA) in Asians, with HLA-G and -E polymorphisms. HLA-G (14 bp Ins/Del rs371194629, +3142 rs1063320, +3187 rs9380142) and HLA-E (rs1264457, and rs2844724) polymorphisms were analyzed in 127 patients with ERA and 381 ethnically matched healthy controls with TaqMan 5'-nuclease assay using allele-specific fluorogenic oligonucleotide probes. HLA-G and -E polymorphisms were not found to be associated with susceptibility to ERA. HLA-G +3187 (rs9380142) G allele was associated with hip arthritis (Pc = 0.04, OR = 2.22, 95%CI = 1.07-4.63) and hip deformity (Pc = 0.02, OR = 2.51, 95%CI = 1.16-5.43). HLA-B*27 was positive in 91. HLA-E rs1264457 G and rs2844724 T alleles may be associated with B*27 positivity in ERA. Among HLA-G, -E haplotypes, frequency of -InsGAAC was significantly higher in patients than healthy controls (Pc = 0.003). In conclusion, HLA-G and HLA-E haplotype -InsGAAC may be associated with susceptibility to ERA and HLA-G +3187 rs9380142 A>G polymorphism may be a poor prognostic marker for progression to hip arthritis and deformity in ERA-JIA.

Early-onset subclinical cardiovascular damage assessed by non-invasive methods in children with Juvenile Idiopathic Arthritis: analytical cross-sectional study.

Chronic inflammation starting early in life and continuing into adulthood may predispose children with Juvenile Idiopathic Arthritis (JIA) to cardiovascular (CV) complications. To compare non-invasive CV risk markers- left ventricular mass index (LVMi), brachial artery flow mediated dilatation (FMD) and carotid artery intima-media thickness (CIMT) between patients with JIA and healthy controls. Measurements of LVMi, CIMT and FMD and lipid profile were compared between 4 and 18 year old 81 patients with JIA and 78 age and sex matched healthy controls. Among 81, 20 had systemic onset, 19 enthesitis related arthritis, 9 polyarticular rheumatoid factor (RF) + ve, 19 polyarticular RF -ve, 11 oligo-articular, and 3 un-differentiated JIA. FMD was significantly lower (p < 0.001), CIMT and LVMi significantly higher in patients (p ≤ 0.001). CIMT showed positive correlation with blood pressure (p = 0.001), disease duration (p ≤ 0.001) and negative correlation with high density lipoprotein (HDL) (p ≤ 0.001). FMD correlated positively with HDL (p = 0.006) and negatively with disease duration (p ≤ 0.001). CIMT (p = 0.017) and FMD (p = 0.04) were significantly worse in active than inactive disease. Children with JIA have worse lipid profile, increased LVMi, CIMT, and reduced brachial artery FMD, suggestive of early cardiovascular dysfunction.

The Seattle Flu Study: a multiarm community-based prospective study protocol for assessing influenza prevalence, transmission and genomic epidemiology.

INTRODUCTION: Influenza epidemics and pandemics cause significant morbidity and mortality. An effective response to a potential pandemic requires the infrastructure to rapidly detect, characterise, and potentially contain new and emerging influenza strains at both an individual and population level. The objective of this study is to use data gathered simultaneously from community and hospital sites to develop a model of how influenza enters and spreads in a population. METHODS AND ANALYSIS: Starting in the 2018-2019 season, we have been enrolling individuals with acute respiratory illness from community sites throughout the Seattle metropolitan area, including clinics, childcare facilities, Seattle-Tacoma International Airport, workplaces, college campuses and homeless shelters. At these sites, we collect clinical data and mid-nasal swabs from individuals with at least two acute respiratory symptoms. Additionally, we collect residual nasal swabs and data from individuals who seek care for respiratory symptoms at four regional hospitals. Samples are tested using a multiplex molecular assay, and influenza whole genome sequencing is performed for samples with influenza detected. Geospatial mapping and computational modelling platforms are in development to characterise the regional spread of influenza and other respiratory pathogens. ETHICS AND DISSEMINATION: The study was approved by the University of Washington's Institutional Review Board (STUDY00006181). Results will be disseminated through talks at conferences, peer-reviewed publications and on the study website (www.seattleflu.org).

Daily Vaginal Swabs and Mobile Phone Sex Report for Assessing HIV Virion Exposure Prospectively Among a Cohort of Young Sexually Active Women in South Africa (HVTN 915).

BACKGROUND: Measurements of HIV exposure could help identify subpopulations at highest risk of acquisition and improve the design of HIV prevention efficacy trials and public health interventions. The HVTN 915 study evaluated the feasibility of self-administered vaginal swabs for detection of HIV virions to assess exposure. METHODS: Fifty 18- to 25-year-old sexually active HIV-seronegative women using contraception were enrolled in Soweto, South Africa. Participants self-administered daily vaginal swabs and answered sexual behavior questions through mobile phone for 90 days. Clinician-administered vaginal swabs, behavioral questionnaires, HIV diagnostic testing, and counseling were performed at 8 clinic visits. Glycogen concentrations assessed adherence to swabbing. Y-chromosome DNA (Yc-DNA) assessed the accuracy of reported condom use. HIV exposure was measured by virion polymerase chain reaction in swabs from 41 women who reported unprotected vaginal sex during follow-up. RESULTS: Glycogen was detected in 315/336 (93.8%) participant-collected and in all clinician-collected swabs. Approximately 20/39 daily swabs (51.3%) linked to mobile reports of unprotected sex tested positive for Yc-DNA, whereas 10/187 swabs collected after 3 days of abstinence or protected sex (5.3%) had detectable Yc-DNA. No participant became HIV infected during the study; yet, exposure to HIV was detected by nucleic acids in 2 vaginal swabs from 1 participant, collected less than 1 hour after coitus. CONCLUSION: There was high adherence to daily vaginal swabbing. Daily mobile surveys had accurate reporting of unprotected sex. Detection of HIV in self-collected vaginal swabs from an uninfected participant demonstrated it was possible to measure HIV exposure, but the detection rate was lower than expected.

Clinical correlates of HLA-B*27 and its subtypes in enthesitis-related arthritis variant of juvenile idiopathic arthritis in south Indian Tamil patients.

AIM: The aim of the study was to assess the distribution of human leukocyte antigen (HLA)-B*27 subtypes and its correlation with disease phenotypes in children with enthesitis-related arthritis variant of juvenile idiopathic arthritis (JIA-ERA). METHOD: One hundred and sixty patients (132 males, 28 females) satisfying the International League Against Rheumatism (ILAR) classification criteria for JIA-ERA were assessed and relevant demographic, clinical and radiographic data were documented. HLA-B*27 typing was done for all the patients and B*27 positive samples were subjected to high-resolution gene sequencing. The effect of duration of illness, HLA-B*27, its subtypes, and gender on the clinical phenotype were analyzed. RESULTS: The mean age of disease onset was 12.69 ± 2.4 years with a male:female ratio of 4.7:1.0. HLA-B*27 was positive in 109/160 patients and HLA-B*27:04 was detected in 63% followed by B*27:05 (30%). Duration of illness was greater in patients with skeletal deformity, hip arthritis, sacroiliitis, cervical spine involvement and acute anterior uveitis (AAU) (P < 0.05). HLA-B*27 positivity was associated with a prolonged course of disease, higher incidence of AAU (14.7% vs 2%, P = 0.015), family history of spondyloarthritis (21.1% vs 5.9%; P = 0.015) and higher erythrocyte sedimentation rate as compared to HLA-B*27 negative patients (P < 0.01). The HLA-B*27:04 and *27:05 positive patients had similar clinical phenotypes. CONCLUSION: Presence of HLA-B*27 and long duration of illness results in skeletal deformity, hip arthritis, sacroiliitis, cervical spine involvement and AAU. HLA-B*27:04 followed by B*27:05 are the most common HLA-B*27 subtypes in our study population and both have a similar clinical phenotype.

The IRF5 rs2004640 (G/T) polymorphism is not a genetic risk factor for systemic lupus erythematosus in population from south India.

Background & objectives: Genetic aberrations disrupting toll-like receptor and interferon homeostasis enhance the risk of systemic lupus erythematosus (SLE). Raised serum interferon-alpha (IFN-α) levels in SLE patients have been ascribed to polymorphism (rs2004640 G/T) in interferon regulatory factor 5 (IRF5) gene, resulting in enhanced transcript splicing. A positive association between IRF5 polymorphism and SLE risk has been reported in many populations. This study was aimed to find out frequency of IRF5 rs2004640 G/T polymorphism in patients with SLE and healthy controls and to assess its influence on susceptibility, clinical and serological characteristics of SLE. Methods: IRF5 rs2004640 (G/T) polymorphism was analyzed in 300 SLE patients and 460 age and sex matched controls by real-time PCR. Results: The IRF5 rs2004640 (G/T) polymorphism did not confer risk of SLE or influence clinical or serological phenotype. However, the mutant allele conferred a borderline risk to develop thrombocytopenia (odds ratio: 2.05, 95% confidence interval: 0.97-4.3, P=0.06) in patients with SLE. Interpretation & conclusions: Our study revealed that the IRF5 rs2004640 polymorphism was not a risk factor for SLE in population from south India. It may, however, be a useful genetic marker for thrombocytopenia in SLE patients. Although we could not demonstrate susceptibility toward lupus in the presence of IRF5 rs2004640 (G/T) polymorphism, further exploration of the genetic variability of IRF5 may help uncover its pathogenic role in Indian SLE patients.

Antiphospholipid Syndrome Complicating Pneumococcal Meningitis.

BACKGROUND: Antiphospholipid syndrome is a multisystem auto-immune disorder characterized by arterial or venous thrombosis in children. CASE CHARACTERISTICS: 11-year-old child with pneumococcal meningitis also had cerebral sinus vein thrombosis and pulmonary artery segmental thrombosis. OBSERVATION: Pro-thrombotic evaluation showed positive lupus anticoagulant at baseline and after 12 weeks. Investigations for lupus were negative at admission and after one year of follow-up. MESSAGE: Antiphospholipid syndrome is a possibility even in thrombosis occurring in the setting of meningitis.