Rangaraj Selvarangan

Genotype Prevalence and Risk Factors for Severe Clinical Adenovirus Infection, United States 2004-2006

BACKGROUNDnRecently, epidemiological and clinical data have revealed important changes with regard to clinical adenovirus infection, including alterations in antigenic presentation, geographical distribution, and virulence of the virus.nnnMETHODSnIn an effort to better understand the epidemiology of clinical adenovirus infection in the United States, we adopted a new molecular adenovirus typing technique to study clinical adenovirus isolates collected from 22 medical facilities over a 25-month period during 2004-2006. A hexon gene sequence typing method was used to characterize 2237 clinical adenovirus-positive specimens, comparing their sequences with those of the 51 currently recognized prototype human adenovirus strains. In a blinded comparison, this method performed well and was much faster than the classic serologic typing method.nnnRESULTSnAmong civilians, the most prevalent adenovirus types were types 3 (prevalence, 34.6%), 2 (24.3%), 1 (17.7%), and 5 (5.3%). Among military trainees, the most prevalent types were types 4 (prevalence, 92.8%), 3 (2.6%), and 21 (2.4%).nnnCONCLUSIONSnFor both populations, we observed a statistically significant increasing trend of adenovirus type 21 detection over time. Among adenovirus isolates recovered from specimens from civilians, 50% were associated with hospitalization, 19.6% with a chronic disease condition, 11% with a bone marrow or solid organ transplantation, 7.4% with intensive care unit stay, and 4.2% with a cancer diagnosis. Multivariable risk factor modeling for adenovirus disease severity found that age <7 years (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.4-7.4), chronic disease (OR, 3.6; 95% CI, 2.6-5.1), recent transplantation (OR, 2.7; 95% CI, 1.3-5.2), and adenovirus type 5 (OR, 2.7; 95% CI, 1.5-4.7) or type 21 infection (OR, 7.6; 95% CI, 2.6-22.3) increased the risk of severe disease.

Effectiveness of Pentavalent and Monovalent Rotavirus Vaccines in Concurrent Use Among US Children <5 Years of Age, 2009–2011

BACKGROUNDnWe assessed vaccine effectiveness (VE) for RotaTeq (RV5; 3 doses) and Rotarix (RV1; 2 doses) at reducing rotavirus acute gastroenteritis (AGE) inpatient and emergency department (ED) visits in US children.nnnMETHODSnWe enrolled children <5 years of age hospitalized or visiting the ED with AGE symptoms from November 2009-June 2010 and from November 2010-June 2011 at 7 medical institutions. Fecal specimens were tested for rotavirus by enzyme immunoassay and genotyped. Vaccination among laboratory-confirmed rotavirus cases was compared with rotavirus-negative AGE controls. Regression models calculated VE estimates for each vaccine, age, ethnicity, genotype, and clinical setting.nnnRESULTSnRV5-specific analyses included 359 rotavirus cases and 1811 rotavirus-negative AGE controls. RV1-specific analyses included 60 rotavirus cases and 155 rotavirus-negative AGE controls. RV5 and RV1 were 84% (95% confidence interval [CI], 78%-88%) and 70% (95% CI, 39%-86%) effective, respectively, against rotavirus-associated ED visits and hospitalizations combined. By clinical setting, RV5 VE against ED and inpatient rotavirus-associated visits was 81% (95% CI, 70%-84%) and 86% (95% CI, 74%-91%), respectively. RV1 was 78% (95% CI, 46%-91%) effective against ED rotavirus disease; study power was insufficient to evaluate inpatient RV1 VE. No waning of immunity was evident during the first 4 years of life for RV5, nor during the first 2 years of life for RV1. RV5 provided genotype-specific protection against each of the predominant strains (G1P[8], G2P[4], G3P[8], G12P[8]), while RV1 VE was statistically significant for the most common genotype, G3P[8].nnnCONCLUSIONSnBoth RV5 and RV1 significantly protected against medically attended rotavirus gastroenteritis in this real-world assessment.

Susceptibilities of Haemophilus influenzae, Streptococcus pneumoniae, including serotype 19A, and Moraxella catarrhalis paediatric isolates from 2005 to 2007 to commonly used antibiotics

OBJECTIVESnThe aim of this study was to evaluate susceptibility to common paediatric antibiotics for Streptococcus pneumoniae, non-typeable Haemophilus influenzae and Moraxella catarrhalis isolated from 2005 through 2007.nnnMETHODSnMicrodilution MIC assays were performed using CLSI-approved methods. S. pneumoniae 19A strains were identified by quellung reaction.nnnRESULTSnAmong 143 non-typeable H. influenzae, 42% produced beta-lactamase. By 2007 breakpoints (PK/PD:CLSI), percentage susceptibility for non-typeable H. influenzae was: ceftriaxone = cefixime = high-dose amoxicillin/clavulanate (all 100%:100%) > standard-dose amoxicillin/clavulanate (91.6%:100%) > cefuroxime axetil (88.1%:99.3%) > cefdinir (83.9%:100%) > trimethoprim/sulfamethoxazole (73.4%:73.4%) >high-dose amoxicillin (58%:58%) > standard-dose amoxicillin (55.2%:58%) > cefprozil (28.7%:83.2%) > cefaclor (3.5%:83.2%) > azithromycin (0%:87.4%). Of 208 S. pneumoniae (42 serotype 19A), 86 were penicillin-susceptible, 60 were penicillin-intermediate and 62 were penicillin-resistant by 2007 CLSI breakpoints. Percentage susceptibility for all S. pneumoniae/19A by PD breakpoints was: ceftriaxone (95.2%/86.1%) > high-dose amoxicillin (89.4%/58.3%) > clindamycin (85%/58.3%) > standard-dose amoxicillin (73.5%/33.3%) > cefuroxime axetil (69.2%/36.1%), cefprozil (67.3%/33.3%) > cefdinir (59.1%/33.3%) > cefixime (57.7%/33.3%) > azithromycin (56.7%/33.3%) > trimethoprim/sulfamethoxazole (50.5%/25%) > penicillin (41.3%/19.4%) > cefaclor (28.8%/8.3%). Percentage M. catarrhalis (n = 62) susceptibility by PK/PD breakpoints was: high-dose amoxicillin/clavulanate = cefixime (100%) > azithromycin (98.4%) > ceftriaxone (96.8%) > standard-dose amoxicillin/clavulanate (88.7%) > cefdinir (80.6%) > cefprozil = cefuroxime axetil (37.1%) > high-dose amoxicillin (11.2%) > cefaclor (6.5%) > standard-dose amoxicillin (4.8%).nnnCONCLUSIONSnDespite high rates of beta-lactamase production among non-typeable H. influenzae and M. catarrhalis, multiple oral treatment options exist for non-typeable H. influenzae and M. catarrhalis. Multidrug-resistant serotype 19A S. pneumoniae ( approximately 20%) limits treatment options for ambulatory S. pneumoniae respiratory disease.

Multicenter clinical evaluation of the novel Alere™ i Influenza A&B isothermal nucleic acid amplification test.

BACKGROUNDnRapid detection of influenza infection is important for patient management and timely anti-viral therapy. Rapid antigen detection tests for influenza have inferior sensitivity when compared to nucleic acid-based amplification tests. An isothermal nucleic acid amplification test that offers the potential for rapid molecular testing at the clinical point-of-care with simple equipment can improve influenza detection rates.nnnOBJECTIVESnTo evaluate the performance of Alere™ i Influenza A&B isothermal nucleic acid amplification test to detect influenza A and B in comparison to viral cell culture as reference method.nnnSTUDY DESIGNnA prospective, multicenter, clinical study to evaluate the clinical performance of the Alere™ i Influenza A&B assay in a point-of-care setting using prospectively enrolled specimens from both children and adults was conducted in seven sites.nnnRESULTSnIn comparison with viral cell culture, the overall sensitivity and specificity of the Alere™ i Influenza A&B assay was 97.8% and 85.6% for the detection of influenza A, and 91.8% and 96.3% for the detection of influenza B, respectively. Following resolution of discrepant results by real-time RT-PCR the sensitivity and specificity of the Alere™ i Influenza A&B assay improved to 99.3% and 98.1% for influenza A, and 97.6% and 100% for influenza B, respectively.nnnCONCLUSIONSnThe Alere™ i Influenza A&B isothermal nucleic acid amplification test is an ideal point-of-care test for influenza detection in children and adults due to its high sensitivity and specificity and ability to generate results within 15 min from specimen receipt.

Molecular Methods and Platforms for Infectious Diseases Testing: A Review of FDA-Approved and Cleared Assays

The superior sensitivity and specificity associated with the use of molecular assays has greatly improved the field of infectious disease diagnostics by providing clinicians with results that are both accurate and rapidly obtained. Herein, we review molecularly based infectious disease diagnostic tests that are Food and Drug Administration approved or cleared and commercially available in the United States as of December 31, 2010. We describe specific assays and their performance, as stated in the Food and Drug Administrations Summary of Safety and Effectiveness Data or the Office of In Vitro Diagnostic Device Evaluation and Safetys decision summaries, product inserts, or peer-reviewed literature. We summarize indications for testing, limitations, and challenges related to implementation in a clinical laboratory setting for a wide variety of common pathogens. The information presented in this review will be particularly useful for laboratories that plan to implement or expand their molecular offerings in the near term.

Severe respiratory illness associated with a nationwide outbreak of enterovirus D68 in the USA (2014): a descriptive epidemiological investigation

n Summaryn n Backgroundn Enterovirus D68 (EV-D68) has been infrequently reported historically, and is typically associated with isolated cases or small clusters of respiratory illness. Beginning in August, 2014, increases in severe respiratory illness associated with EV-D68 were reported across the USA. We aimed to describe the clinical, epidemiological, and laboratory features of this outbreak, and to better understand the role of EV-D68 in severe respiratory illness.n n n Methodsn We collected regional syndromic surveillance data for epidemiological weeks 23 to 44, 2014, (June 1 to Nov 1, 2014) and hospital admissions data for epidemiological weeks 27 to 44, 2014, (June 29 to Nov 1, 2014) from three states: Missouri, Illinois and Colorado. Data were also collected for the same time period of 2013 and 2012. Respiratory specimens from severely ill patients nationwide, who were rhinovirus-positive or enterovirus-positive in hospital testing, were submitted between Aug 1, and Oct 31, 2014, and typed by molecular sequencing. We collected basic clinical and epidemiological characteristics of EV-D68 cases with a standard data collection form submitted with each specimen. We compared patients requiring intensive care with those who did not, and patients requiring ventilator support with those who did not. Mantel-Haenszel χ2 tests were used to test for statistical significance.n n n Findingsn Regional and hospital-level data from Missouri, Illinois, and Colorado showed increases in respiratory illness between August and September, 2014, compared with in 2013 and 2012. Nationwide, 699 (46%) of 1529 patients tested were confirmed as EV-D68. Among the 614 EV-D68-positive patients admitted to hospital, age ranged from 3 days to 92 years (median 5 years). Common symptoms included dyspnoea (n=513 [84%]), cough (n=500 [81%]), and wheezing (n=427 [70%]); 294 (48%) patients had fever. 338 [59%] of 574 were admitted to intensive care units, and 145 (28%) of 511 received ventilator support; 322 (52%) of 614 had a history of asthma or reactive airway disease; 200 (66%) of 304 patients with a history of asthma or reactive airway disease required intensive care compared with 138 (51%) of 270 with no history of asthma or reactive airway disease (p=0·0004). Similarly, 89 (32%) of 276 patients with a history of asthma or reactive airway disease required ventilator support compared with 56 (24%) of 235 patients with no history of asthma or reactive airway disease (p=0·039).n n n Interpretationn In 2014, EV-D68 caused widespread severe respiratory illness across the USA, disproportionately affecting those with asthma. This unexpected event underscores the need for robust surveillance of enterovirus types, enabling improved understanding of virus circulation and disease burden.n n n Fundingn None.n n

Epidemiologic Association Between FUT2 Secretor Status and Severe Rotavirus Gastroenteritis in Children in the United States

IMPORTANCEnA genetic polymorphism affecting FUT2 secretor status in approximately one-quarter of humans of European descent affects the expression of histo-blood group antigens on the mucosal epithelia of human respiratory, genitourinary, and digestive tracts. These histo-blood group antigens serve as host receptor sites necessary for attachment and infection of some pathogens, including norovirus.nnnOBJECTIVEnWe investigated whether an association exists between FUT2 secretor status and laboratory-confirmed rotavirus infections in US children.nnnDESIGN, SETTING, AND PARTICIPANTSnMulticenter case-control observational study involving active surveillance at 6 US pediatric medical institutions in the inpatient and emergency department clinical settings. We enrolled 1564 children younger than 5 years with acute gastroenteritis (diarrhea and/or vomiting) and 818 healthy controls frequency matched by age and month, from December 1, 2011, through March 31, 2013.nnnMAIN OUTCOMES AND MEASURESnPaired fecal-saliva specimens were tested for rotavirus and for secretor status. Comparisons were made between rotavirus test-positive cases and healthy controls stratified by ethnicity and vaccination status. Adjusted multivariable analyses assessed the preventive association of secretor status against severe rotavirus gastroenteritis.nnnRESULTSnOne (0.5%) of 189 rotavirus test-positive cases was a nonsecretor, compared with 188 (23%) of 818 healthy control participants (Pu2009<u2009.001). Healthy control participants of Hispanic ethnicity were significantly less likely to be nonsecretors (13%) compared with healthy children who were not of Hispanic ethnicity (25%) (Pu2009<u2009.001). After controlling for vaccination and other factors, children with the nonsecretor FUT2 polymorphism appeared statistically protected (98% [95% CI, 84%-100%]) against severe rotavirus gastroenteritis.nnnCONCLUSIONS AND RELEVANCEnSevere rotavirus gastroenteritis was virtually absent among US children who had a genetic polymorphism that inactivates FUT2 expression on the intestinal epithelium. We observed a strong epidemiologic association among children with rotavirus gastroenteritis compared with healthy control participants. The exact cellular mechanism behind this epidemiologic association remains unclear, but evidence suggests that it may be rotavirus genotype specific. The lower prevalence of nonsecretors among Hispanic children may translate to an enhanced burden of rotavirus gastroenteritis among this group. Our findings may have bearing on our full understanding of rotavirus infections and the effects of vaccination in diverse populations.

Innate Susceptibility to Norovirus Infections Influenced by FUT2 Genotype in a United States Pediatric Population

BACKGROUNDnNorovirus is a leading cause of acute gastroenteritis (AGE). Noroviruses bind to gut histo-blood group antigens (HBGAs), but only 70%-80% of individuals have a functional copy of the FUT2 (secretor) gene required for gut HBGA expression; these individuals are known as secretors. Susceptibility to some noroviruses depends on FUT2 secretor status, but the population impact of this association is not established.nnnMETHODSnFrom December 2011 to November 2012, active AGE surveillance was performed at 6 geographically diverse pediatric sites in the United States. Case patients aged <5 years were recruited from emergency departments and inpatient units; age-matched healthy controls were recruited at well-child visits. Salivary DNA was collected to determine secretor status and genetic ancestry. Stool was tested for norovirus by real-time reverse transcription polymerase chain reaction. Norovirus genotype was then determined by sequencing.nnnRESULTSnNorovirus was detected in 302 of 1465 (21%) AGE cases and 52 of 826 (6%) healthy controls. Norovirus AGE cases were 2.8-fold more likely than norovirus-negative controls to be secretors (P < .001) in a logistic regression model adjusted for ancestry, age, site, and health insurance. Secretors comprised all 155 cases and 21 asymptomatic infections with the most prevalent norovirus, GII.4. Control children of Meso-American ancestry were more likely than children of European or African ancestry to be secretors (96% vs 74%; P < .001).nnnCONCLUSIONSnFUT2 status is associated with norovirus infection and varies by ancestry. GII.4 norovirus exclusively infected secretors. These findings are important to norovirus vaccine trials and design of agents that may block norovirus-HBGA binding.

Macrolide-Resistant Mycoplasma pneumoniae, United States.

Macrolide-resistant Mycoplasma pneumoniae (MRMP) is highly prevalent in Asia and is now being reported from Europe. Few data on MRMP are available in the United States. Using genotypic and phenotypic methods, we detected high-level MRMP in 13.2% of 91 M. pneumoniae–positive specimens from 6 US locations.

Molecular epidemiology and clinical presentation of human adenovirus infections in Kansas City children

BACKGROUNDnA significant increase in adenovirus detection among patients at the Childrens Mercy Hospital, Kansas City was observed between June 2007 and January 2008.nnnOBJECTIVEnTo molecularly characterize the human adenoviruses and describe their association with clinical illness in children.nnnSTUDY DESIGNnOne hundred adenovirus-positive specimens from 79 children were typed by hexon gene sequence typing method. Restriction enzyme analysis (REA) was performed on isolates of HAdV-3, -7 and -14 to identify genomic variants. Medical records were reviewed to understand the clinical illnesses associated with adenovirus serotypes and genome types.nnnRESULTSnThe most prevalent HAdV serotypes were HAdV-3 (37%), HAdV-7 (25%), HAdV-1 (16%), HAdV-2 (8%). HAdV infection was common in children ≤3 years of age (71%) versus children >3 years (29%). Majority of the HAdV-infected children were hospitalized (78%); 22/79 (28%) stayed >3 days and 8/79 (10%) required intensive care unit stay. Hospitalization rates for HAdV-3 (36%) and HAdV-7 (25%) were comparable. REA data indicated that HAdV-3a2 was the predominant HAdV-3 genome type. Two novel genomic variants of HAdV-3 exhibiting unique BglII or BstEII profiles were identified in isolates from patients with bronchiolitis. All HAdV-7 and -14 isolates were identified as corresponding to genome types 7d2 and 14p1, respectively.nnnCONCLUSIONSnIn Kansas City, we noticed an increase in the incidence of HAdV-7 (25%; n=24/98) infections compared to the previous two years (6%; n=6/107). Two new genomic variants of HAdV-3 appear to have emerged in our area and seem to be associated with lower respiratory tract infections in children.