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BACKGROUND: Herpes simplex virus type 2 (HSV-2) infections are associated with increased risk of HIV transmission. We determined HSV-2 prevalence, incidence and associated risk factors, incidence among persons with indeterminate results, and prevalence of HSV-2/HIV co-infection among young adults (18-34 years) and adolescents (16-17 years) enrolled in an HIV incidence cohort study in western Kenya. METHODS: Participants (n = 1106; 846 adults) were screened and those HIV-1 negative were enrolled and followed-up quarterly for one year. HSV-2 was assessed using the Kalon enzyme immunoassay. HSV-2 incidence was calculated separately among HSV-2 seronegative participants and those indeterminate at baseline. Logistic regression was used to estimate the odds of HSV-2 infection and Poisson regression was used to assess HSV-2 incidence and associated factors. RESULTS: Overall, HSV-2 prevalence was 26.6% [95% confidence interval (CI): 23.9-29.4] and was higher in adults (31.5% [95% CI: 28.3-34.9]) than adolescents (10.7% [95% CI: 7.1-15.3]). Factors associated with prevalent HSV-2 included female gender, increasing age, HIV infection, history of sexually transmitted infection, low level of education, multiple sexual partners, and being married, divorced, separated or widowed. Overall HSV-2 incidence was 4.0 per 100 person-years (/100PY) 95% CI: 2.7-6.1 and was higher in adults (4.5/100PY) and females (5.1/100PY). In multivariable analysis only marital status was associated with HSV-2 incidence. Among 45 participants with indeterminate HSV-2 results at baseline, 22 seroconverted, resulting in an incidence rate of 53.2 /100PY [95% CI: 35.1-80.9]. Inclusion of indeterminate results almost doubled the overall incidence rate to 7.8 /100 PY [95% CI: 5.9-10.5]. Prevalence of HIV/HSV-2 co-infection was higher in female adults than female adolescents (17.1 [95% CI: 13.6-21.0] versus 3.4 [95% CI: 1.1-7.8]). CONCLUSION: The high incidence rate among persons with indeterminate results underscores the public health concerns for HSV-2 spread and underreporting of the HSV-2 burden. Careful consideration is needed when interpreting HSV-2 serology results in these settings.
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Density of upper respiratory colonization with Streptococcus pneumoniae and its role in the diagnosis of pneumococcal pneumonia among children aged <5 years in the PERCH StudyBaggett HC, Watson NL, Deloria Knoll M, Brooks WA, Feikin DR, Hammitt LL, Howie SR, Kotloff KL, Levine OS, Madhi SA, Murdoch DR, Scott JA, Thea DM, Antonio M, Awori JO, Baillie VL, DeLuca AN, Driscoll AJ, Duncan J, Ebruke BE, Goswami D, Higdon MM, Karron RA, Moore DP, Morpeth SC, Mulindwa JM, Park DE, Paveenkittiporn W, Piralam B, Prosperi C, Sow SO, Tapia MD, Zaman K, Zeger SL, O’Brien KL.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S317-s327.
Background.: Previous studies suggested an association between upper airway pneumococcal colonization density and pneumococcal pneumonia, but data in children are limited. Using data from the Pneumonia Etiology Research for Child Health (PERCH) study, we assessed this potential association. Methods.: PERCH is a case-control study in 7 countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. Cases were children aged 1-59 months hospitalized with World Health Organization-defined severe or very severe pneumonia. Controls were randomly selected from the community. Microbiologically confirmed pneumococcal pneumonia (MCPP) was confirmed by detection of pneumococcus in a relevant normally sterile body fluid. Colonization density was calculated with quantitative polymerase chain reaction analysis of nasopharyngeal/oropharyngeal specimens. Results.: Median colonization density among 56 cases with MCPP (MCPP cases; 17.28 x 106 copies/mL) exceeded that of cases without MCPP (non-MCPP cases; 0.75 x 106) and controls (0.60 x 106) (each P < .001). The optimal density for discriminating MCPP cases from controls using the Youden index was >6.9 log10 copies/mL; overall, the sensitivity was 64% and the specificity 92%, with variable performance by site. The threshold was lower (>/=4.4 log10 copies/mL) when MCPP cases were distinguished from controls who received antibiotics before specimen collection. Among the 4035 non-MCPP cases, 500 (12%) had pneumococcal colonization density >6.9 log10 copies/mL; above this cutoff was associated with alveolar consolidation at chest radiography, very severe pneumonia, oxygen saturation <92%, C-reactive protein >/=40 mg/L, and lack of antibiotic pretreatment (all P< .001). Conclusions.: Pneumococcal colonization density >6.9 log10 copies/mL was strongly associated with MCPP and could be used to improve estimates of pneumococcal pneumonia prevalence in childhood pneumonia studies. Our findings do not support its use for individual diagnosis in a clinical setting.
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Standardization of clinical assessment and sample collection across all PERCH study sitesCrawley J, Prosperi C,
Baggett HC, Brooks WA, Deloria Knoll M, Hammitt LL, Howie SR, Kotloff KL, Levine OS, Madhi SA, Murdoch DR, O’Brien KL, Thea DM, Awori JO,
Bunthi C, DeLuca AN, Driscoll AJ, Ebruke BE, Goswami D, Hidgon MM, Karron RA, Kazungu S, Kourouma N, Mackenzie G, Moore DP, Mudau A, Mwale M, Nahar K, Park DE, Piralam B, Seidenberg P, Sylla M,
Feikin DR, Scott JA.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S228-s237.
Background.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. Methods.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. Results.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were >/=80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (>/=89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. Conclusions.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.
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Bayesian estimation of pneumonia etiology: Epidemiologic considerations and applications to the Pneumonia Etiology Research for Child Health StudyDeloria Knoll M, Fu W, Shi Q, Prosperi C, Wu Z, Hammitt LL,
Feikin DR,
Baggett HC, Howie SR, Scott JA, Murdoch DR, Madhi SA, Thea DM, Brooks WA, Kotloff KL, Li M, Park DE, Lin W, Levine OS, O’Brien KL, Zeger SL.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S213-s227.
In pneumonia, specimens are rarely obtained directly from the infection site, the lung, so the pathogen causing infection is determined indirectly from multiple tests on peripheral clinical specimens, which may have imperfect and uncertain sensitivity and specificity, so inference about the cause is complex. Analytic approaches have included expert review of case-only results, case-control logistic regression, latent class analysis, and attributable fraction, but each has serious limitations and none naturally integrate multiple test results. The Pneumonia Etiology Research for Child Health (PERCH) study required an analytic solution appropriate for a case-control design that could incorporate evidence from multiple specimens from cases and controls and that accounted for measurement error. We describe a Bayesian integrated approach we developed that combined and extended elements of attributable fraction and latent class analyses to meet some of these challenges and illustrate the advantage it confers regarding the challenges identified for other methods.
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Evaluation of pneumococcal load in blood by polymerase chain reaction for the diagnosis of pneumococcal pneumonia in young children in the PERCH StudyDeloria Knoll M, Morpeth SC, Scott JA, Watson NL, Park DE,
Baggett HC, Brooks WA, Feikin DR, Hammitt LL, Howie SR, Kotloff KL, Levine OS, O’Brien KL, Thea DM, Ahmed D, Antonio M, Awori JO, Baillie VL, Chipeta J, Deluca AN, Dione M, Driscoll AJ, Higdon MM, Jatapai A, Karron RA, Mazumder R, Moore DP, Mwansa J, Nyongesa S, Prosperi C, Seidenberg P, Siludjai D, Sow SO, Tamboura B, Zeger SL, Murdoch DR, Madhi SA.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S357-s367.
Background.: Detection of pneumococcus by lytA polymerase chain reaction (PCR) in blood had poor diagnostic accuracy for diagnosing pneumococcal pneumonia in children in 9 African and Asian sites. We assessed the value of blood lytA quantification in diagnosing pneumococcal pneumonia. Methods.: The Pneumonia Etiology Research for Child Health (PERCH) case-control study tested whole blood by PCR for pneumococcus in children aged 1-59 months hospitalized with signs of pneumonia and in age-frequency matched community controls. The distribution of load among PCR-positive participants was compared between microbiologically confirmed pneumococcal pneumonia (MCPP) cases, cases confirmed for nonpneumococcal pathogens, nonconfirmed cases, and controls. Receiver operating characteristic analyses determined the “optimal threshold” that distinguished MCPP cases from controls. Results.: Load was available for 290 of 291 cases with pneumococcal PCR detected in blood and 273 of 273 controls. Load was higher in MCPP cases than controls (median, 4.0 x 103 vs 0.19 x 103 copies/mL), but overlapped substantially (range, 0.16-989.9 x 103 copies/mL and 0.01-551.9 x 103 copies/mL, respectively). The proportion with high load (>/=2.2 log10 copies/mL) was 62.5% among MCPP cases, 4.3% among nonconfirmed cases, 9.3% among cases confirmed for a nonpneumococcal pathogen, and 3.1% among controls. Pneumococcal load in blood was not associated with respiratory tract illness in controls (P = .32). High blood pneumococcal load was associated with alveolar consolidation on chest radiograph in nonconfirmed cases, and with high (>6.9 log10 copies/mL) nasopharyngeal/oropharyngeal load and C-reactive protein >/=40 mg/L (both P < .01) in nonconfirmed cases but not controls. Conclusions.: Quantitative pneumococcal PCR in blood has limited diagnostic utility for identifying pneumococcal pneumonia in individual children, but may be informative in epidemiological studies.
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Safety of induced sputum collection in children hospitalized with severe or very severe pneumoniaDeLuca AN, Hammitt LL, Kim J, Higdon MM,
Baggett HC, Brooks WA, Howie SR, Deloria Knoll M, Kotloff KL, Levine OS, Madhi SA, Murdoch DR, Scott JA, Thea DM, Amornintapichet T, Awori JO, Chuananon S, Driscoll AJ, Ebruke BE, Hossain L, Jahan Y, Kagucia EW, Kazungu S, Moore DP, Mudau A, Mwananyanda L, Park DE, Prosperi C, Seidenberg P, Sylla M, Tapia MD, Zaman SM, O’Brien KL.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S301-s308.
Background.: Induced sputum (IS) may provide diagnostic information about the etiology of pneumonia. The safety of this procedure across a heterogeneous population with severe pneumonia in low- and middle-income countries has not been described. Methods.: IS specimens were obtained as part a 7-country study of the etiology of severe and very severe pneumonia in hospitalized children <5 years of age. Rigorous clinical monitoring was done before, during, and after the procedure to record oxygen requirement, oxygen saturation, respiratory rate, consciousness level, and other evidence of clinical deterioration. Criteria for IS contraindications were predefined and serious adverse events (SAEs) were reported to ethics committees and a central safety monitor. Results.: A total of 4653 IS procedures were done among 3802 children. Thirteen SAEs were reported in relation to collection of IS, or 0.34% of children with at least 1 IS specimen collected (95% confidence interval, 0.15%-0.53%). A drop in oxygen saturation that required supplemental oxygen was the most common SAE. One child died after feeding was reinitiated 2 hours after undergoing sputum induction; this death was categorized as “possibly related” to the procedure. Conclusions.: The overall frequency of SAEs was very low, and the nature of most SAEs was manageable, demonstrating a low-risk safety profile for IS collection even among severely ill children in low-income-country settings. Healthcare providers should monitor oxygen saturation and requirements during and after IS collection, and assess patients prior to reinitiating feeding after the IS procedure, to ensure patient safety.
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Effect of point-of-care CD4 cell count results on linkage to care and antiretroviral initiation during a home-based HIV testing campaign: a non-blinded, cluster-randomised trialDesai MA, Okal DO,
Rose CE, Ndivo R, Oyaro B, Otieno FO,
Williams T,
Chen RT,
Zeh C,
Samandari T.
Lancet HIV. 2017 May 31.
BACKGROUND: HIV disease staging with referral laboratory-based CD4 cell count testing is a key barrier to the initiation of antiretroviral treatment (ART). Point-of-care CD4 cell counts can improve linkage to HIV care among people living with HIV, but its effect has not been assessed with a randomised controlled trial in the context of home-based HIV counselling and testing (HBCT). METHODS: We did a two-arm, cluster-randomised, controlled efficacy trial in two districts of western Kenya with ongoing HBCT. Housing compounds were randomly assigned (1:1) to point-of-care CD4 cell counts (366 compounds with 417 participants) or standard-of-care (318 compounds with 353 participants) CD4 cell counts done at one of three referral laboratories serving the study catchment area. In each compound, we enrolled people with HIV not engaged in care in the previous 6 months. All participants received post-test counselling and referral for HIV care. Point-of-care test participants received additional counselling on the result, including ART eligibility if CD4 was less than 350 cells per muL, the cutoff in Kenyan guidelines. Participants were interviewed 6 months after enrolment to ascertain whether they sought HIV care, verified through chart reviews at 23 local clinics. The prevalence of loss to follow-up at 6 months (LTFU) was listed as the main outcome in the study protocol. We analysed linkage to care at 6 months (defined as 1-LTFU) as the primary outcome. All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02515149. FINDINGS: We enrolled 770 participants between July 1, 2013, and Feb 28, 2014. 692 (90%) had verified linkage to care status and 78 (10%) were lost to follow-up. Of 371 participants in the point-of-care group, 215 (58%) had linked to care within 6 months versus 108 (34%) of 321 in the standard-of-care group (Cox proportional multivariable hazard ratio [HR] 2.14, 95% CI 1.67-2.74; log rank p<0.0001). INTERPRETATION: Point-of-care CD4 cell counts in a resource-limited HBCT setting doubled linkage to care and thereby improved ART initiation. Given the substantial economic and logistic hindrances to providing ART for all people with HIV in resource-limited settings in the near term, point of care CD4 cell counts might have a role in prioritising care and improving linkage to care. FUNDING: US Centers for Disease Control and Prevention.
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First newborn baby to receive experimental therapies survives Ebola virus diseaseDornemann J, Burzio C, Ronsse A, Sprecher A, De Clerck H, Van Herp M, Kolie MC, Yosifiva V, Caluwaerts S,
McElroy AK, Antierens A.
J Infect Dis. 2017 Jan 15;215(2):171-174.
A neonate born to an Ebola virus-positive woman was diagnosed with Ebola virus infection on her first day of life. The patient was treated with monoclonal antibodies (ZMapp), a buffy coat transfusion from an Ebola survivor, and the broad-spectrum antiviral GS-5734. On day 20, a venous blood specimen tested negative for Ebola virus by quantitative reverse-transcription polymerase chain reaction. The patient was discharged in good health on day 33 of life. Further follow-up consultations showed age-appropriate weight gain and neurodevelopment at the age of 12 months. This patient is the first neonate documented to have survived congenital infection with Ebola virus.
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The effect of antibiotic exposure and specimen volume on the detection of bacterial pathogens in children with pneumoniaDriscoll AJ, Deloria Knoll M, Hammitt LL,
Baggett HC, Brooks WA, Feikin DR, Kotloff KL, Levine OS, Madhi SA, O’Brien KL, Scott JA, Thea DM, Howie SR, Adrian PV, Ahmed D, DeLuca AN, Ebruke BE, Gitahi C, Higdon MM, Kaewpan A, Karani A, Karron RA, Mazumder R, McLellan J, Moore DP, Mwananyanda L, Park DE, Prosperi C,
Rhodes J, Saifullah M, Seidenberg P, Sow SO, Tamboura B, Zeger SL, Murdoch DR.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S368-s377.
Background.: Antibiotic exposure and specimen volume are known to affect pathogen detection by culture. Here we assess their effects on bacterial pathogen detection by both culture and polymerase chain reaction (PCR) in children. Methods.: PERCH (Pneumonia Etiology Research for Child Health) is a case-control study of pneumonia in children aged 1-59 months investigating pathogens in blood, nasopharyngeal/oropharyngeal (NP/OP) swabs, and induced sputum by culture and PCR. Antibiotic exposure was ascertained by serum bioassay, and for cases, by a record of antibiotic treatment prior to specimen collection. Inoculated blood culture bottles were weighed to estimate volume. Results.: Antibiotic exposure ranged by specimen type from 43.5% to 81.7% in 4223 cases and was detected in 2.3% of 4863 controls. Antibiotics were associated with a 45% reduction in blood culture yield and approximately 20% reduction in yield from induced sputum culture. Reduction in yield of Streptococcus pneumoniae from NP culture was approximately 30% in cases and approximately 32% in controls. Several bacteria had significant but marginal reductions (by 5%-7%) in detection by PCR in NP/OP swabs from both cases and controls, with the exception of S. pneumoniae in exposed controls, which was detected 25% less frequently compared to nonexposed controls. Bacterial detection in induced sputum by PCR decreased 7% for exposed compared to nonexposed cases. For every additional 1 mL of blood culture specimen collected, microbial yield increased 0.51% (95% confidence interval, 0.47%-0.54%), from 2% when volume was </=1 mL to approximately 6% for >/=3 mL. Conclusions.: Antibiotic exposure and blood culture volume affect detection of bacterial pathogens in children with pneumonia and should be accounted for in studies of etiology and in clinical management.
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Standardization of laboratory methods for the PERCH StudyDriscoll AJ, Karron RA, Morpeth SC, Bhat N, Levine OS,
Baggett HC, Brooks WA, Feikin DR, Hammitt LL, Howie SR, Knoll MD, Kotloff KL, Madhi SA, Scott JA, Thea DM, Adrian PV, Ahmed D, Alam M, Anderson TP, Antonio M, Baillie VL, Dione M, Endtz HP, Gitahi C, Karani A, Kwenda G, Maiga AA, McClellan J, Mitchell JL, Morailane P, Mugo D, Mwaba J, Mwansa J, Mwarumba S, Nyongesa S, Panchalingam S, Rahman M,
Sawatwong P, Tamboura B, Toure A,
Whistler T, O’Brien KL, Murdoch DR.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S245-s252.
The Pneumonia Etiology Research for Child Health study was conducted across 7 diverse research sites and relied on standardized clinical and laboratory methods for the accurate and meaningful interpretation of pneumonia etiology data. Blood, respiratory specimens, and urine were collected from children aged 1-59 months hospitalized with severe or very severe pneumonia and community controls of the same age without severe pneumonia and were tested with an extensive array of laboratory diagnostic tests. A standardized testing algorithm and standard operating procedures were applied across all study sites. Site laboratories received uniform training, equipment, and reagents for core testing methods. Standardization was further assured by routine teleconferences, in-person meetings, site monitoring visits, and internal and external quality assurance testing. Targeted confirmatory testing and testing by specialized assays were done at a central reference laboratory.
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Chest radiograph findings in childhood pneumonia cases from the multisite PERCH StudyFancourt N, Deloria Knoll M,
Baggett HC, Brooks WA,
Feikin DR, Hammitt LL, Howie SR, Kotloff KL, Levine OS, Madhi SA, Murdoch DR, Scott JA, Thea DM, Awori JO, Barger-Kamate B, Chipeta J, DeLuca AN, Diallo M, Driscoll AJ, Ebruke BE, Higdon MM, Jahan Y, Karron RA, Mahomed N, Moore DP, Nahar K, Naorat S, Ominde MS, Park DE, Prosperi C, Wa Somwe S, Thamthitiwat S, Zaman SM, Zeger SL, O’Brien KL.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S262-s270.
Background: Chest radiographs (CXRs) are frequently used to assess pneumonia cases. Variations in CXR appearances between epidemiological settings and their correlation with clinical signs are not well documented. Methods: The Pneumonia Etiology Research for Child Health project enrolled 4232 cases of hospitalized World Health Organization (WHO)-defined severe and very severe pneumonia from 9 sites in 7 countries (Bangladesh, the Gambia, Kenya, Mali, South Africa, Thailand, and Zambia). At admission, each case underwent a standardized assessment of clinical signs and pneumonia risk factors by trained health personnel, and a CXR was taken that was interpreted using the standardized WHO methodology. CXRs were categorized as abnormal (consolidation and/or other infiltrate), normal, or uninterpretable. Results: CXRs were interpretable in 3587 (85%) cases, of which 1935 (54%) were abnormal (site range, 35%-64%). Cases with abnormal CXRs were more likely than those with normal CXRs to have hypoxemia (45% vs 26%), crackles (69% vs 62%), tachypnea (85% vs 80%), or fever (20% vs 16%) and less likely to have wheeze (30% vs 38%; all P < .05). CXR consolidation was associated with a higher case fatality ratio at 30-day follow-up (13.5%) compared to other infiltrate (4.7%) or normal (4.9%) CXRs. Conclusions: Clinically diagnosed pneumonia cases with abnormal CXRs were more likely to have signs typically associated with pneumonia. However, CXR-normal cases were common, and clinical signs considered indicative of pneumonia were present in substantial proportions of these cases. CXR-consolidation cases represent a group with an increased likelihood of death at 30 days post-discharge.
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Standardized interpretation of chest radiographs in cases of pediatric pneumonia from the PERCH StudyFancourt N, Deloria Knoll M, Barger-Kamate B, de Campo J, de Campo M, Diallo M, Ebruke BE,
Feikin DR, Gleeson F, Gong W, Hammitt LL, Izadnegahdar R, Kruatrachue A, Madhi SA, Manduku V, Matin FB, Mahomed N, Moore DP, Mwenechanya M, Nahar K, Oluwalana C, Ominde MS, Prosperi C, Sande J, Suntarattiwong P, O’Brien KL.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S253-s261.
Background.: Chest radiographs (CXRs) are a valuable diagnostic tool in epidemiologic studies of pneumonia. The World Health Organization (WHO) methodology for the interpretation of pediatric CXRs has not been evaluated beyond its intended application as an endpoint measure for bacterial vaccine trials. Methods.: The Pneumonia Etiology Research for Child Health (PERCH) study enrolled children aged 1-59 months hospitalized with WHO-defined severe and very severe pneumonia from 7 low- and middle-income countries. An interpretation process categorized each CXR into 1 of 5 conclusions: consolidation, other infiltrate, both consolidation and other infiltrate, normal, or uninterpretable. Two members of a 14-person reading panel, who had undertaken training and standardization in CXR interpretation, interpreted each CXR. Two members of an arbitration panel provided additional independent reviews of CXRs with discordant interpretations at the primary reading, blinded to previous reports. Further discordance was resolved with consensus discussion. Results.: A total of 4172 CXRs were obtained from 4232 cases. Observed agreement for detecting consolidation (with or without other infiltrate) between primary readers was 78% (kappa = 0.50) and between arbitrators was 84% (kappa = 0.61); agreement for primary readers and arbitrators across 5 conclusion categories was 43.5% (kappa = 0.25) and 48.5% (kappa = 0.32), respectively. Disagreement was most frequent between conclusions of other infiltrate and normal for both the reading panel and the arbitration panel (32% and 30% of discordant CXRs, respectively). Conclusions.: Agreement was similar to that of previous evaluations using the WHO methodology for detecting consolidation, but poor for other infiltrates despite attempts at a rigorous standardization process.
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Is higher viral load in the upper respiratory tract associated with severe pneumonia? Findings From the PERCH StudyFeikin DR, Fu W, Park DE, Shi Q, Higdon MM,
Baggett HC, Brooks WA, Deloria Knoll M, Hammitt LL, Howie SR, Kotloff KL, Levine OS, Madhi SA, Scott JA, Thea DM, Adrian PV, Antonio M, Awori JO, Baillie VL, DeLuca AN, Driscoll AJ, Ebruke BE, Goswami D, Karron RA, Li M, Morpeth SC, Mwaba J, Mwansa J, Prosperi C,
Sawatwong P, Sow SO, Tapia MD,
Whistler T, Zaman K, Zeger SL, O’ Brien KL, Murdoch DR.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S337-s346.
Background.: The etiologic inference of identifying a pathogen in the upper respiratory tract (URT) of children with pneumonia is unclear. To determine if viral load could provide evidence of causality of pneumonia, we compared viral load in the URT of children with World Health Organization-defined severe and very severe pneumonia and age-matched community controls. Methods.: In the 9 developing country sites, nasopharyngeal/oropharyngeal swabs from children with and without pneumonia were tested using quantitative real-time polymerase chain reaction for 17 viruses. The association of viral load with case status was evaluated using logistic regression. Receiver operating characteristic (ROC) curves were constructed to determine optimal discriminatory viral load cutoffs. Viral load density distributions were plotted. Results.: The mean viral load was higher in cases than controls for 7 viruses. However, there was substantial overlap in viral load distribution of cases and controls for all viruses. ROC curves to determine the optimal viral load cutoff produced an area under the curve of <0.80 for all viruses, suggesting poor to fair discrimination between cases and controls. Fatal and very severe pneumonia cases did not have higher viral load than less severe cases for most viruses. Conclusions.: Although we found higher viral loads among pneumonia cases than controls for some viruses, the utility in using viral load of URT specimens to define viral pneumonia was equivocal. Our analysis was limited by lack of a gold standard for viral pneumonia.
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Pneumonia kills more children each year worldwide than any other disease. Nonetheless, accurately determining the causes of childhood pneumonia has remained elusive. Over the past century, the focus of pneumonia etiology research has shifted from studies of lung aspirates and postmortem specimens intent on identifying pneumococcal disease to studies of multiple specimen types distant from the lung that are tested for multiple pathogens. Some major challenges facing modern pneumonia etiology studies include the use of nonspecific and variable case definitions, poor access to pathologic lung tissue and to specimens from fatal cases, poor diagnostic accuracy of assays (especially when testing nonpulmonary specimens), and the interpretation of results when multiple pathogens are detected in a given individual. The future of childhood pneumonia etiology research will likely require integrating data from complementary approaches, including applications of advanced molecular diagnostics and vaccine probe studies, as well as a renewed emphasis on lung aspirates from radiologically confirmed pneumonia and postmortem examinations.
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Background: Measles, a vaccine-preventable disease that can cause severe complications, was declared eliminated from the United States in 2000. The last published summary of US measles epidemiology was during 2001-2008. We summarized US measles epidemiology during 2009-2014. Methods: We compared demographic, vaccination, and virologic data on confirmed measles cases reported to the Centers for Disease Control and Prevention during January 1, 2009-December 31, 2014 and January 1, 2001-December 31, 2008. Results: During 2009-2014, 1264 confirmed measles cases were reported in the United States, including 275 importations from 58 countries and 66 outbreaks. The annual median number of cases and outbreaks during this period was 130 (range, 55-667 cases) and 10 (range, 4-23 outbreaks), respectively, compared with an annual median of 56 cases (P = .08) and 4 outbreaks during 2001-2008 (P = .04). Among US-resident case-patients during 2009-2014, children aged 12-15 months had the highest measles incidence (65 cases; 8.3 cases/million person-years), and infants aged 6-11 months had the second highest incidence (86 cases; 7.3 cases/million person-years). During 2009-2014, 865 (74%) of 1173 US-resident case-patients were unvaccinated and 188 (16%) had unknown vaccination status; of 917 vaccine-eligible US-resident case-patients, 600 (65%) were reported as having philosophical or religious objections to vaccination. Conclusions: Although the United States has maintained measles elimination since 2000, measles outbreaks continue to occur globally, resulting in imported cases and potential spread. The annual median number of cases and outbreaks more than doubled during 2009-2014 compared with the earlier postelimination years. To maintain elimination, it will be necessary to maintain high 2-dose vaccination coverage, continue case-based surveillance, and monitor the patterns and rates of vaccine exemption.
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[No abstract]
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Despite tremendous advances in diagnostic laboratory technology, identifying the pathogen(s) causing pneumonia remains challenging because the infected lung tissue cannot usually be sampled for testing. Consequently, to obtain information about pneumonia etiology, clinicians and researchers test specimens distant to the site of infection. These tests may lack sensitivity (eg, blood culture, which is only positive in a small proportion of children with pneumonia) and/or specificity (eg, detection of pathogens in upper respiratory tract specimens, which may indicate asymptomatic carriage or a less severe syndrome, such as upper respiratory infection). While highly sensitive nucleic acid detection methods and testing of multiple specimens improve sensitivity, multiple pathogens are often detected and this adds complexity to the interpretation as the etiologic significance of results may be unclear (ie, the pneumonia may be caused by none, one, some, or all of the pathogens detected). Some of these challenges can be addressed by adjusting positivity rates to account for poor sensitivity or incorporating test results from controls without pneumonia to account for poor specificity. However, no classical analytic methods can account for measurement error (ie, sensitivity and specificity) for multiple specimen types and integrate the results of measurements for multiple pathogens to produce an accurate understanding of etiology. We describe the major analytic challenges in determining pneumonia etiology and review how the common analytical approaches (eg, descriptive, case-control, attributable fraction, latent class analysis) address some but not all challenges. We demonstrate how these limitations necessitate a new, integrated analytical approach to pneumonia etiology data.
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Should controls with respiratory symptoms be excluded from case-control studies of pneumonia etiology? Reflections from the PERCH StudyHigdon MM, Hammitt LL, Deloria Knoll M,
Baggett HC, Brooks WA, Howie SR, Kotloff KL, Levine OS, Madhi SA, Murdoch DR, Scott JA, Thea DM, Driscoll AJ, Karron RA, Park DE, Prosperi C, Zeger SL, O’Brien KL,
Feikin DR.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S205-s212.
Many pneumonia etiology case-control studies exclude controls with respiratory illness from enrollment or analyses. Herein we argue that selecting controls regardless of respiratory symptoms provides the least biased estimates of pneumonia etiology. We review 3 reasons investigators may choose to exclude controls with respiratory symptoms in light of epidemiologic principles of control selection and present data from the Pneumonia Etiology Research for Child Health (PERCH) study where relevant to assess their validity. We conclude that exclusion of controls with respiratory symptoms will result in biased estimates of etiology. Randomly selected community controls, with or without respiratory symptoms, as long as they do not meet the criteria for case-defining pneumonia, are most representative of the general population from which cases arose and the least subject to selection bias.
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Association of C-reactive protein with bacterial and respiratory syncytial virus-associated pneumonia among children aged <5 years in the PERCH StudyHigdon MM, Le T, O’Brien KL, Murdoch DR, Prosperi C,
Baggett HC, Brooks WA,
Feikin DR, Hammitt LL, Howie SR, Kotloff KL, Levine OS, Scott JA, Thea DM, Awori JO, Baillie VL, Cascio S, Chuananon S, DeLuca AN, Driscoll AJ, Ebruke BE, Endtz HP, Kaewpan A, Kahn G, Karani A, Karron RA, Moore DP, Park DE, Rahman MZ, Salaudeen R, Seidenberg P, Somwe SW, Sylla M, Tapia MD, Zeger SL, Deloria Knoll M, Madhi SA.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S378-s386.
Background.: Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study. Methods.: We measured serum CRP levels in cases with World Health Organization-defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for “confirmed” bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid culture or polymerase chain reaction [PCR]) compared to “RSV pneumonia” (nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia). Receiver operating characteristic (ROC) curves were constructed to assess the performance of elevated CRP in distinguishing these cases. Results.: Among 601 human immunodeficiency virus (HIV)-negative tested controls, 3% had CRP >/=40 mg/L. Among 119 HIV-negative cases with confirmed bacterial pneumonia, 77% had CRP >/=40 mg/L compared with 17% of 556 RSV pneumonia cases. The ROC analysis produced an area under the curve of 0.87, indicating very good discrimination; a cut-point of 37.1 mg/L best discriminated confirmed bacterial pneumonia (sensitivity 77%) from RSV pneumonia (specificity 82%). CRP >/=100 mg/L substantially improved specificity over CRP >/=40 mg/L, though at a loss to sensitivity. Conclusions.: Elevated CRP was positively associated with confirmed bacterial pneumonia and negatively associated with RSV pneumonia in PERCH. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral-associated pneumonia needs further study.
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Shiga toxin-producing Escherichia coli (STEC) causes an estimated 265 000 infections in the United States annually. Of emerging non-O157:H7 STEC serotypes, O26 is the most commonly recognized. During an outbreak of STEC O26 in Oregon in 2015, we used syndromic surveillance data to supplement case finding by laboratory reporting. From 157 records retrieved by querying syndromic surveillance data, we detected 4 confirmed and 5 suspected cases. However, none of the suspected cases were confirmed by stool culture, and by the time that the data were being analyzed, the confirmed cases were already known to investigators. Syndromic surveillance data can potentially supplement case finding during outbreaks of foodborne disease. To be an effective case-finding strategy, timely completion of all steps, including collecting specimens from suspected cases, should be performed in real time.
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Retinol binding protein and vitamin D were measured in children aged <5 years hospitalized with lower respiratory tract infection and respiratory syncytial virus and/or human metapneumovirus detections. Low vitamin levels were observed in 50% of the children and were associated with significantly elevated risk of the need for intensive care unit admission and invasive mechanical ventilation.
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OBJECTIVES: Drug-susceptibility testing (DST) of Mycobacterium tuberculosis is necessary for identifying drug-resistant tuberculosis, administering effective treatment regimens, and preventing the spread of drug-resistant tuberculosis. DST is recommended for all culture-confirmed cases of tuberculosis. We examined trends in delayed and unreported DST results in the Centers for Disease Control and Prevention’s National Tuberculosis Surveillance System. METHODS: We analyzed culture-confirmed tuberculosis cases reported to the National Tuberculosis Surveillance System during 1993-2014 for annual trends in initial DST reporting for first-line antituberculosis drugs and trends in on-time, delayed, and unreported results. We defined on-time reporting as DST results received during the same calendar year in which the patient’s case was reported or </=4 months after the calendar year ended and delayed reporting as DST results received after the calendar year. We compared cases with on-time, delayed, and unreported DST results by patient and tuberculosis program characteristics. RESULTS: The proportion of cases with reported results for all first-line antituberculosis drugs increased during 1993-2011. Reporting of pyrazinamide results was lower than reporting of other drugs. However, during 2000-2012, of 134 787 tuberculosis cases reported to the National Tuberculosis Surveillance System, reporting was on time for 125 855 (93.4%) cases, delayed for 5332 (4.0%) cases, and unreported for 3600 (2.7%) cases. CONCLUSIONS: Despite increases in the proportion of cases with on-time DST results, delayed and unreported results persisted. Carefully assessing causes for delayed and unreported DST results should lead to more timely reporting of drug-resistant tuberculosis.
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In Arizona during 1997-2013, coccidioidomycosis increased from 21 to 90 cases/100,000 population, but coccidioidomycosis-associated deaths remained stable at 3-6 deaths/million population. We used the capture-recapture method by using death certificates and hospital discharge data to more fully estimate the total number of coccidioidomycosis-attributable deaths and compared this with published estimates. Death certificates were included if any cause of death included coccidioidomycosis; hospital discharge data deaths were included if any discharge diagnosis included coccidioidomycosis and laboratory confirmation. Among deaths during 2008-2013, we identified 529 coccidioidomycosis-attributable deaths from death certificates and 560 from hospital discharge data, with 251 deaths identified in both databases. Capture-recapture estimated 1,178 total coccidioidomycosis-attributable deaths, compared with 164 deaths (underlying cause of death) or 529 deaths (any cause of death) on death certificates. Coccidioidomycosis-attributable deaths are underreported from two- to sevenfold on Arizona death certificates, demonstrating an education need for death certifiers to document coccidioidomycosis mortality.
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Measles (rubeola) continues to be endemic and epidemic in many regions of the world. Measles is primarily a disease of childhood, but it can also affect adult populations, and therefore it is important that both adult and pediatric hospitalist physicians be able to recognize it. Although the disease is rarely encountered in the United States, measles infection can spread rapidly across vulnerable populations. In addition, infected adults can develop complications that may require hospitalization for treatment. This review summarizes the typical clinical course and complications of measles infection, along with recommendations for diagnosis and management for both adult and pediatric hospitalists. Journal of Hospital Medicine 2017;12:472-476.
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Candida auris is an emerging, multidrug-resistant threat. The pharmacodynamics of three antifungal classes against nine C. auris strains was explored using a murine invasive candidiasis model. The total drug median PD target associated with net stasis was a fluconazole AUC/MIC of 26, amphotericin B Cmax/MIC of 0.9, and micafungin AUC/MIC of 54. The micafungin PD targets for C. auris were >/=20-fold lower than other Candida species in this animal model. Clinically relevant micafungin exposures produced the most killing among the three classes.
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Antiviral drug resistance HBV variants (HBV-DR) occur spontaneously in chronic hepatitis B (CHB) patients and after exposure to nucleos(t)ide analogues (NUCs). We determined the prevalence of HBV-DR variants among participants of the Hepatitis B Research Network (HBRN) Cohort Study conducted at 21 sites in the United States (US) and Canada. Samples obtained from 1342 CHB participants aged >/=18 years, and who were currently not receiving NUCs, were tested for HBV-DR variants by Sanger sequencing. In addition, next generation sequencing (NGS) was used to characterize HBV-DR variants from 66 participants with and 66 participants with no prior NUC exposure matched for HBV genotype and HBV DNA level. Half the participants were men, 75% Asian, 26% HBeAg-positive. Primary HBV-DR variants were detected by Sanger sequencing in 16 (1.2%) participants: 2/142 (1.4%) with and 14/1200 (1.2%) without prior NUC exposure; only 1 of these 16 had a secondary variant. In total, 23 (1.7%) participants had secondary variants, including 1 with prior NUC experience. In the subset of 132 participants, NGS detected HBV-DR variants in a higher proportion of participants: primary variants in 18 (13.6%) [8 (12.1%) with, and 10 (15.2%) without prior NUC therapy], and secondary variants in 10 (7.6%) participants. Based on Sanger sequencing, prevalence of primary HBV-DR variants is low (1.2%) among adults with CHB in US/Canada. The similar low prevalence of HBV-DR variants in participants with and without NUC treatment suggests transmission of these variants is uncommon.
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Thailand national guidelines for the prevention of mother-to-child transmission of HIV 2017
Lolekha R, Chokephaibulkit K, Phanuphak N, Chaithongwongwatthana S, Kietiburanakul S, Chetchotisakd P, Boonsuk S.
Asian Biomedicine. 2017 April;11(2):145-159.
Background: Thailand validated the elimination of mother-to-child transmission (MTCT) of HIV in June 2016 (meeting World Health Organization target < 2%). The Thailand National HIV Guidelines Working Group issued a new version of its national Prevention of MTCT guidelines in December 2016 aimed to reduce MTCT rate to less than 1% by 2020. Objectives: To organize national stakeholders for a new MTCT of HIV to further reduce MTCT of HIV Methods: The US CDC, Division of Global HIV/AIDS, medical scores, the Thai Red Cross AIDS Research Centers, and the Ministry of Public Health collaborated to develop Thailand National Guidelines for prevention of MTCT of HIV Results: The guidelines included recommending initiation antepartum highly active antiretroviral therapy (HAART) containing tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC) plus efavirenz (EFV) regardless of CD4 cell count as soon as HIV is diagnosed for antiretroviral treatment (ART) naive HIV-infected pregnant women. An alternative regimen is TDF or zidovudine (AZT) plus 3TC plus lopinavir/ritonavir (LPV/r) for the HIV-infected pregnant woman suspected to have NNRTI resistance. Treatment should be started immediately irrespective of gestational age and continue after delivery for life. Raltegravir is recommended in addition to HAART regimen for HIV-infected pregnant women who present late at ANC (gestational age (GA) >= 32 weeks) or those who have viral load (VL) > 1000 copies/mL at GA > 32 weeks. HIV-infected pregnant women who conceive while receiving HAART should continue this effective treatment regimen during pregnancy. HIV-infected pregnant women who present in labor and do not receiving HAART should receive single-dose nevira pine (SD-NVP) immediately along with oral AZT, initiate and continue HAART for life. Infants born to HIV-infected mothers are categorized into two groups (high risk vs. standard risk) based on their risk for MTCT. High MTCT risk is defined as an infant whose mother has VL > 50 copies/mL at GA > 36 weeks or has received HAART less than 12 weeks prior to delivery, or has poor ART adherence. These infants should be initiated AZT plus 3TC plus NVP for six weeks after delivery. Infants with standard MTCT risk should receive AZT syrup for 4 weeks. Exclusive formula feeding is recommended for all HIV-exposed infants. Conclusions: In addition to ARV therapy, other coordinated care are essential to further reduce MTCT of HIV in Thailand.
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[No abstract]
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The incremental value of repeated induced sputum and gastric aspirate samples for the diagnosis of pulmonary tuberculosis in young children with acute community-acquired pneumoniaMoore DP, Higdon MM, Hammitt LL, Prosperi C, DeLuca AN, Da Silva P, Baillie VL, Adrian PV, Mudau A, Deloria Knoll M,
Feikin DR, Murdoch DR, O’Brien KL, Madhi SA.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S309-s316.
Background.: Mycobacterium tuberculosis (Mtb) contributes to the pathogenesis of childhood acute community-acquired pneumonia in settings with a high tuberculosis burden. The incremental value of a repeated induced sputum (IS) sample, compared with a single IS or gastric aspirate (GA) sample, is not well known. Methods.: Two IS samples were obtained for Mtb culture from children enrolled as cases in the Pneumonia Etiology Research for Child Health (PERCH) study in South Africa. Nonstudy attending physicians requested GA if pulmonary tuberculosis was clinically suspected. We compared the Mtb yield of 2 IS samples to that of 1 IS sample and GA samples. Results: . Twenty-seven (3.0%) culture-confirmed pulmonary tuberculosis cases were identified among 906 children investigated with IS and GA samples for Mtb. Results from 2 IS samples were available for 719 children (79.4%). Of 12 culture-confirmed pulmonary tuberculosis cases identified among children with >/=2 IS samples, 4 (33.3%) were negative at the first IS sample. In head-to-head comparisons among children with both GA and IS samples collected, the yield of 1 GA sample (8 of 427; 1.9%) was similar to that of 1 IS sample (5 of 427, 1.2%), and the yield of 2 GA samples (10 of 300; 3.3%) was similar to that of 2 IS samples (5 of 300; 1.7%). IS samples identified 8 (42.1%) of the 19 culture-confirmed pulmonary tuberculosis cases that were identified through submission of IS and GA samples. Conclusions.: A single IS sample underestimated the presence of Mtb in children hospitalized with severe or very severe pneumonia. Detection of Mtb is enhanced by combining 2 IS with GA sample collections in young children with acute severe pneumonia.
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Detection of pneumococcal DNA in blood by polymerase chain reaction for diagnosing pneumococcal pneumonia in young children from low- and middle-income countriesMorpeth SC, Deloria Knoll M, Scott JA, Park DE, Watson NL,
Baggett HC, Brooks WA,
Feikin DR, Hammitt LL, Howie SR, Kotloff KL, Levine OS, Madhi SA, O’Brien KL, Thea DM, Adrian PV, Ahmed D, Antonio M, Bunthi C, DeLuca AN, Driscoll AJ, Githua LP, Higdon MM, Kahn G, Karani A, Karron RA, Kwenda G, Makprasert S, Mazumder R, Moore DP, Mwansa J, Nyongesa S, Prosperi C, Sow SO, Tamboura B, Whistler T, Zeger SL, Murdoch DR.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S347-s356.
Background.: We investigated the performance of polymerase chain reaction (PCR) on blood in the diagnosis of pneumococcal pneumonia among children from 7 low- and middle-income countries. Methods.: We tested blood by PCR for the pneumococcal autolysin gene in children aged 1-59 months in the Pneumonia Etiology Research for Child Health (PERCH) study. Children had World Health Organization-defined severe or very severe pneumonia or were age-frequency-matched community controls. Additionally, we tested blood from general pediatric admissions in Kilifi, Kenya, a PERCH site. The proportion PCR-positive was compared among cases with microbiologically confirmed pneumococcal pneumonia (MCPP), cases without a confirmed bacterial infection (nonconfirmed), cases confirmed for nonpneumococcal bacteria, and controls. Results.: In PERCH, 7.3% (n = 291/3995) of cases and 5.5% (n = 273/4987) of controls were blood pneumococcal PCR-positive (P < .001), compared with 64.3% (n = 36/56) of MCPP cases and 6.3% (n = 243/3832) of nonconfirmed cases (P < .001). Blood pneumococcal PCR positivity was higher in children from the 5 African countries (5.5%-11.5% among cases and 5.3%-10.2% among controls) than from the 2 Asian countries (1.3% and 1.0% among cases and 0.8% and 0.8% among controls). Among Kilifi general pediatric admissions, 3.9% (n = 274/6968) were PCR-positive, including 61.7% (n = 37/60) of those with positive blood cultures for pneumococcus. Discussion.: The utility of pneumococcal PCR on blood for diagnosing childhood pneumococcal pneumonia in the 7 low- and middle-income countries studied is limited by poor specificity and by poor sensitivity among MCPP cases.
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The diagnostic utility of induced sputum microscopy and culture in childhood pneumoniaMurdoch DR, Morpeth SC, Hammitt LL, Driscoll AJ, Watson NL,
Baggett HC, Brooks WA, Deloria Knoll M,
Feikin DR, Kotloff KL, Levine OS, Madhi SA, O’Brien KL, Scott JA, Thea DM, Adrian PV, Ahmed D, Alam M, Awori JO, DeLuca AN, Higdon MM, Karron RA, Kwenda G, Machuka EM, Makprasert S, McLellan J, Moore DP, Mwaba J, Mwarumba S, Park DE, Prosperi C, Sangwichian O, Sissoko S, Tapia MD, Zeger SL, Howie SR.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S280-s288.
Background.: Sputum microscopy and culture are commonly used for diagnosing the cause of pneumonia in adults but are rarely performed in children due to difficulties in obtaining specimens. Induced sputum is occasionally used to investigate lower respiratory infections in children but has not been widely used in pneumonia etiology studies. Methods.: We evaluated the diagnostic utility of induced sputum microscopy and culture in patients enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study, a large study of community-acquired pneumonia in children aged 1-59 months. Comparisons were made between induced sputum samples from hospitalized children with radiographically confirmed pneumonia and children categorized as nonpneumonia (due to the absence of prespecified clinical and laboratory signs and absence of infiltrate on chest radiograph). Results.: One induced sputum sample was available for analysis from 3772 (89.1%) of 4232 suspected pneumonia cases enrolled in PERCH. Of these, sputum from 2608 (69.1%) met the quality criterion of <10 squamous epithelial cells per low-power field, and 1162 (44.6%) had radiographic pneumonia. Induced sputum microscopy and culture results were not associated with radiographic pneumonia, regardless of prior antibiotic use, stratification by specific bacteria, or interpretative criteria used. Conclusions.: The findings of this study do not support the culture of induced sputum specimens as a diagnostic tool for pneumonia in young children as part of routine clinical practice.
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Microscopic analysis and quality assessment of induced sputum from children with pneumonia in the PERCH StudyMurdoch DR, Morpeth SC, Hammitt LL, Driscoll AJ, Watson NL,
Baggett HC, Brooks WA, Deloria Knoll M,
Feikin DR, Kotloff KL, Levine OS, Madhi SA, O’Brien KL, Scott JA, Thea DM, Ahmed D, Awori JO, DeLuca AN, Ebruke BE, Higdon MM, Jorakate P, Karron RA, Kazungu S, Kwenda G, Hossain L,
Makprasert S, Moore DP, Mudau A, Mwaba J, Panchalingam S, Park DE, Prosperi C, Salaudeen R, Toure A, Zeger SL, Howie SR.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S271-s279.
Background.: It is standard practice for laboratories to assess the cellular quality of expectorated sputum specimens to check that they originated from the lower respiratory tract. The presence of low numbers of squamous epithelial cells (SECs) and high numbers of polymorphonuclear (PMN) cells are regarded as indicative of a lower respiratory tract specimen. However, these quality ratings have never been evaluated for induced sputum specimens from children with suspected pneumonia. Methods.: We evaluated induced sputum Gram stain smears and cultures from hospitalized children aged 1-59 months enrolled in a large study of community-acquired pneumonia. We hypothesized that a specimen representative of the lower respiratory tract will contain smaller quantities of oropharyngeal flora and be more likely to have a predominance of potential pathogens compared to a specimen containing mainly saliva. The prevalence of potential pathogens cultured from induced sputum specimens and quantity of oropharyngeal flora were compared for different quantities of SECs and PMNs. Results.: Of 3772 induced sputum specimens, 2608 (69%) had <10 SECs per low-power field (LPF) and 2350 (62%) had >25 PMNs per LPF, measures traditionally associated with specimens from the lower respiratory tract in adults. Using isolation of low quantities of oropharyngeal flora and higher prevalence of potential pathogens as markers of higher quality, <10 SECs per LPF (but not >25 PMNs per LPF) was the microscopic variable most associated with high quality of induced sputum. Conclusions.: Quantity of SECs may be a useful quality measure of induced sputum from young children with pneumonia.
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Mycoplasma hominis Infections transmitted through amniotic tissue productNovosad SA,
Basavaraju SV,
Annambhotla P, Mohr M,
Halpin A, Foy L, Chmielewski R,
Winchell JM,
Benitez AJ,
Morrison SS,
Johnson T, Crabb DM, Ratliff AE, Waites K,
Kuehnert MJ.
Clin Infect Dis. 2017 May 31.
Background: Mycoplasma hominis is a commensal genitourinary tract organism that can cause infections outside the genitourinary tract. We investigated a cluster of M. hominis surgical site infections in patients who underwent spine surgery, all associated with amniotic tissue linked to a common donor. Methods: Laboratory tests of tissue product from the donor, including culture, quantitative real-time PCR (qPCR), and whole genome sequencing were performed. Use of this amniotic tissue product was reviewed. A multi-state investigation to identify additional cases and locate any unused products was conducted. Results: Twenty-seven tissue product vials from a donor were distributed to facilities in seven states; at least 20 vials from this donor were used in 14 patients. Of these, 4/14 (29%) developed surgical site infections, including two M. hominis infections. M. hominis was detected by culture and qPCR in two unused vials from the donor. Sequencing indicated >99% similarity between patient and unopened vial isolates. For five of 27 (19%) vials, the final disposition could not be confirmed. Conclusions: M. hominis was transmitted through amniotic tissue from a single donor to two recipients. Current routine donor screening and product testing does not detect all potential pathogens. Clinicians should be aware that M. hominis can cause surgical site infections, and may not be detected by routine clinical cultures. The lack of a standardized system to track tissue products in healthcare facilities limits the ability of public health agencies to respond to outbreaks and investigate other adverse events associated with these products.
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Introduction to the epidemiologic considerations, analytic methods, and foundational results from the Pneumonia Etiology Research for Child Health StudyO’Brien KL,
Baggett HC, Brooks WA,
Feikin DR, Hammitt LL, Howie SR, Deloria Knoll M, Kotloff KL, Levine OS, Madhi SA, Murdoch DR, Scott JA, Thea DM, Zeger SL.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S179-s184.
[No abstract]
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Colonization density of the upper respiratory tract as a predictor of pneumonia-Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jiroveciiPark DE,
Baggett HC, Howie SR, Shi Q, Watson NL, Brooks WA, Deloria Knoll M, Hammitt LL, Kotloff KL, Levine OS, Madhi SA, Murdoch DR, O’Brien KL, Scott JA, Thea DM, Ahmed D, Antonio M, Baillie VL, DeLuca AN, Driscoll AJ, Fu W, Gitahi CW, Olutunde E, Higdon MM, Hossain L, Karron RA, Maiga AA, Maloney SA, Moore DP, Morpeth SC, Mwaba J, Mwenechanya M, Prosperi C, Sylla M, Thamthitiwat S, Zeger SL,
Feikin DR.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S328-s336.
Background.: There is limited information on the association between colonization density of upper respiratory tract colonizers and pathogen-specific pneumonia. We assessed this association for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii. Methods.: In 7 low- and middle-income countries, nasopharyngeal/oropharyngeal swabs from children with severe pneumonia and age-frequency matched community controls were tested using quantitative polymerase chain reaction (PCR). Differences in median colonization density were evaluated using the Wilcoxon rank-sum test. Density cutoffs were determined using receiver operating characteristic curves. Cases with a pathogen identified from lung aspirate culture or PCR, pleural fluid culture or PCR, blood culture, and immunofluorescence for P. jirovecii defined microbiologically confirmed cases for the given pathogens. Results.: Higher densities of H. influenzae were observed in both microbiologically confirmed cases and chest radiograph (CXR)-positive cases compared to controls. Staphylococcus aureus and P. jirovecii had higher densities in CXR-positive cases vs controls. A 5.9 log10 copies/mL density cutoff for H. influenzae yielded 86% sensitivity and 77% specificity for detecting microbiologically confirmed cases; however, densities overlapped between cases and controls and positive predictive values were poor (<3%). Informative density cutoffs were not found for S. aureus and M. catarrhalis, and a lack of confirmed case data limited the cutoff identification for P. jirovecii. Conclusions.: There is evidence for an association between H. influenzae colonization density and H. influenzae-confirmed pneumonia in children; the association may be particularly informative in epidemiologic studies. Colonization densities of M. catarrhalis, S. aureus, and P. jirovecii are unlikely to be of diagnostic value in clinical settings.
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We conducted a systematic review and meta-analysis of the association between serosorting and HIV infection among HIV-negative men who have sex with men (MSM). Compared to no condomless anal sex (i.e., consistent condom use or no anal sex), serosorting was associated with increased HIV risk (RR = 1.64, 95% CI 1.37-1.96). Compared to condomless discordant anal sex, serosorting was associated with reduced HIV risk (RR = 0.46, 95% CI 0.33-0.65). Serosorting may be an important harm reduction strategy when condoms are not consistently used, but can be harmful if HIV-negative MSM who consistently use condoms shift to using serosorting as their primary prevention strategy. The protective effects of serosorting and ways in which MSM are operationalizing serosorting are becoming more complex as additional factors affecting risk are considered (e.g., durable viral load suppression, PrEP). Understanding the potential risk and benefit of serosorting continues to be important, particularly within the context of other prevention strategies.
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High rate of treatment completion in program settings with 12-dose weekly isoniazid and rifapentine (3HP) for latent Mycobacterium tuberculosis infectionSandul AL,
Nwana N, Holcombe JM,
Lobato MN,
Marks S, Webb R, Wang SH,
Stewart B, Griffin P, Hunt G,
Shah N, Marco A, Patil N, Mukasa L,
Moro RN,
Jereb J,
Mase S,
Chorba T,
Bamrah-Morris S,
Ho CS.
Clin Infect Dis. 2017 May 30.
Background: RCTs demonstrated the newest LTBI regimen, 12 weekly doses of directly observed isoniazid and rifapentine (3HP), as efficacious as 9 months of isoniazid (9H) with a greater completion rate (82% versus 69%); however, 3HP has not been assessed in routine health care settings. Methods: Observational cohort of LTBI patients receiving 3HP through 16 US programs was used to assess treatment completion, adverse drug reactions (ADRs), and factors associated with treatment discontinuation. Results: Of 3288 patients eligible to complete 3HP, 2867 (87.2%) completed treatment. Children 2-17 years had the highest completion rate, 94.5% (155/164). Patients reporting homelessness had a completion rate of 81.2% (147/181). In univariable analyses, discontinuation was lowest among children (relative risk [RR], 0.44 [95% CI, 0.23-0.85]; P = .014), and highest in persons >/=65 years (RR, 1.72 [95% CI, 1.25-2.35] P = .001). In multivariable analyses, discontinuation was lowest among contacts of patients with TB disease (adjusted relative risk [ARR], 0.68 [95% CI, 0.52-0.89]; P = .005), and students (ARR, 0.45 [95% CI, 0.21-0.98]; P = .044); highest with incarceration (ARR, 1.43 [95% CI, 1.08-1.89]; P=.013) and homelessness (ARR, 1.72 [95% CI, 1.25-2.39]; P = .001). ADRs were reported by 1174 (35.7%) patients, of whom 891 (76.0%) completed treatment. Conclusions: Completion of 3HP in routine health care settings was greater overall than rates reported from clinical trials, and greater than historically observed using other regimens among reportedly nonadherent populations. Widespread use of 3HP for LTBI treatment could accelerate elimination of TB disease in the United States.
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BACKGROUND: Stigma, criminalisation and a lack of data on drug use contribute to the “invisibility” of people who inject drugs (PWID) and make HIV prevention and treatment service delivery challenging. We aimed to confirm locations where PWID congregate in Cape Town, eThekwini and Tshwane (South Africa) and to estimate PWID population sizes within selected electoral wards in these areas to inform South Africa’s first multi-site HIV prevention project for PWID. METHODS: Field workers (including PWID peers) interviewed community informants to identify suspected injecting locations in selected electoral wards in each city and then visited these locations and interviewed PWID. Interviews were used to gather information about the accessibility of sterile injecting equipment, location coordinates and movement patterns. We used the Delphi method to obtain final population size estimates for the mapped wards based on estimates from wisdom of the crowd methods, the literature and programmatic data. RESULTS: Between January and April 2015, we mapped 45 wards. Tshwane teams interviewed 39 PWID in 12 wards, resulting in an estimated number of accessible PWID ranging from 568 to 1431. In eThekwini, teams interviewed 40 PWID in 15 wards with an estimated number of accessible PWID ranging from 184 to 350. The Cape Town team interviewed 61 PWID in 18 wards with an estimated number of accessible PWID ranging between 398 and 503. Sterile needles were only available at one location. Almost all needles were bought from pharmacies. Between 80 and 86% of PWID frequented more than one location per day. PWID who reported movement visited a median of three locations a day. CONCLUSIONS: Programmatic mapping led by PWID peers can be used effectively to identify and reach PWID and build relationships where access to HIV prevention commodities for PWID is limited. PWID reported limited access to sterile injecting equipment, highlighting an important HIV prevention need. Programmatic mapping data show that outreach programmes should be flexible and account for the mobile nature of PWID populations. The PWID population size estimates can be used to develop service delivery targets and as baseline measures.
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Vital Signs: Health care-associated Legionnaires’ disease surveillance data from 20 states and a large metropolitan area – United States, 2015Soda EA,
Barskey AE,
Shah PP,
Schrag S,
Whitney CG,
Arduino MJ,
Reddy SC,
Kunz JM,
Hunter CM,
Raphael BH,
Cooley LA.
MMWR Morb Mortal Wkly Rep. 2017 Jun 09;66(22):584-589.
BACKGROUND: Legionnaires’ disease, a severe pneumonia, is typically acquired through inhalation of aerosolized water containing Legionella bacteria. Legionella can grow in the complex water systems of buildings, including health care facilities. Effective water management programs could prevent the growth of Legionella in building water systems. METHODS: Using national surveillance data, Legionnaires’ disease cases were characterized from the 21 jurisdictions (20 U.S. states and one large metropolitan area) that reported exposure information for >/=90% of 2015 Legionella infections. An assessment of whether cases were health care-associated was completed; definite health care association was defined as hospitalization or long-term care facility residence for the entire 10 days preceding symptom onset, and possible association was defined as any exposure to a health care facility for a portion of the 10 days preceding symptom onset. All other Legionnaires’ disease cases were considered unrelated to health care. RESULTS: A total of 2,809 confirmed Legionnaires’ disease cases were reported from the 21 jurisdictions, including 85 (3%) definite and 468 (17%) possible health care-associated cases. Among the 21 jurisdictions, 16 (76%) reported 1-21 definite health care-associated cases per jurisdiction. Among definite health care-associated cases, the majority (75, 88%) occurred in persons aged >/=60 years, and exposures occurred at 72 facilities (15 hospitals and 57 long-term care facilities). The case fatality rate was 25% for definite and 10% for possible health care-associated Legionnaires’ disease. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Exposure to Legionella from health care facility water systems can result in Legionnaires’ disease. The high case fatality rate of health care-associated Legionnaires’ disease highlights the importance of case prevention and response activities, including implementation of effective water management programs and timely case identification.
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Uptake of and factors associated with direct-acting antiviral therapy among patients in the Chronic Hepatitis Cohort Study, 2014 to 2015Spradling PR,
Xing J, Rupp LB,
Moorman AC, Gordon SC, Lu M,
Teshale EH, Boscarino JA, Schmidt MA, Daida YG,
Holmberg SD.
J Clin Gastroenterol. 2017 Jun 05.
BACKGROUND: Limited information is available describing the uptake of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection among patients in general US health care settings. We determined the proportion of HCV-infected patients in the Chronic Hepatitis Cohort Study prescribed DAAs in 2014, who initiated treatment and identified characteristics associated with treatment initiation. METHODS: Uptake was defined as the proportion of HCV-infected patients with at least 1 clinical encounter in 2013 who were prescribed a DAA regimen during 2014 and initiated the regimen by August 2015. Using multivariable analysis, we examined demographic and clinical characteristics associated with receipt of DAAs. RESULTS: The cohort comprised 9508 patients; 544 (5.7%) started a DAA regimen. Higher annual income [adjusted odds ratios (aOR) 2.3 for income>$50K vs. <$30K], higher Fibrosis-4 score (aORs, 2.1, 2.0, and 1.4 for Fibrosis-4, >5.88, 3.25 to 5.88, 2.0 to 3.25, respectively, vs. <2.0), genotype 2 infection (aOR 2.2 vs. genotype 1), pre-2014 treatment failure (aOR 2.0 vs. treatment-naive), and human immunodeficiency virus (HIV) coinfection (aOR 1.8 vs. HCV monoinfection) were associated with DAA initiation. Black race/ethnicity (aOR 0.7 vs. whites) and Medicaid coverage (aOR 0.5 vs. private insurance) were associated with noninitiation. Sex, age, comorbidity, previous liver transplant, and duration of follow-up were not associated with receipt of DAAs. CONCLUSIONS: Among patients in these general US health care settings, uptake of DAA therapy was low in 2014, and especially so among minority and Medicaid patients. Systemic efforts to improve access to DAAs for all patients are essential to reduce morbidity and mortality from HCV infection.
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Limited utility of polymerase chain reaction in induced sputum specimens for determining the causes of childhood pneumonia in resource-poor settings: Findings from the Pneumonia Etiology Research for Child Health (PERCH) StudyThea DM, Seidenberg P, Park DE, Mwananyanda L, Fu W, Shi Q,
Baggett HC, Brooks WA,
Feikin DR, Howie SR, Knoll MD, Kotloff KL, Levine OS, Madhi SA, O’Brien KL, Scott JA, Antonio M, Awori JO, Baillie VL, DeLuca AN, Driscoll AJ, Higdon MM, Hossain L, Jahan Y, Karron RA, Kazungu S, Li M, Moore DP, Morpeth SC, Ofordile O, Prosperi C, Sangwichian O, Sawatwong P, Sylla M, Tapia MD, Zeger SL, Murdoch DR, Hammitt LL.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S289-s300.
Background.: Sputum examination can be useful in diagnosing the cause of pneumonia in adults but is less well established in children. We sought to assess the diagnostic utility of polymerase chain reaction (PCR) for detection of respiratory viruses and bacteria in induced sputum (IS) specimens from children hospitalized with severe or very severe pneumonia. Methods.: Among children aged 1-59 months, we compared organism detection by multiplex PCR in IS and nasopharyngeal/oropharyngeal (NP/OP) specimens. To assess whether organism presence or density in IS specimens was associated with chest radiographic evidence of pneumonia (radiographic pneumonia), we compared prevalence and density in IS specimens from children with radiographic pneumonia and children with suspected pneumonia but without chest radiographic changes or clinical or laboratory findings suggestive of pneumonia (nonpneumonia group). Results.: Among 4232 cases with World Health Organization-defined severe or very severe pneumonia, we identified 1935 (45.7%) with radiographic pneumonia and 573 (13.5%) with nonpneumonia. The organism detection yield was marginally improved with IS specimens (96.2% vs 92.4% for NP/OP specimens for all viruses combined [P = .41]; 96.9% vs 93.3% for all bacteria combined [P = .01]). After accounting for presence in NP/OP specimens, no organism was detected more frequently in the IS specimens from the radiographic pneumonia compared with the nonpneumonia cases. Among high-quality IS specimens, there were no statistically significant differences in organism density, except with cytomegalovirus, for which there was a higher quantity in the IS specimens from cases with radiographic pneumonia compared with the nonpneumonia cases (median cycle threshold value, 27.9 vs 28.5, respectively; P = .01). Conclusions.: Using advanced molecular methods with IS specimens provided little additional diagnostic information beyond that obtained with NP/OP swab specimens.
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Perceived message effectiveness to evaluate updated concepts for a national HIV testing campaign for African American women
Uhrig JD, Leeks KD, Stryker JE, Shadle J, Bann CM.
J Commun Healthc. 2017 :1-11.
The U.S. Centers for Disease Control and Prevention launched Take Charge. Take the Test.?, a national, communication campaign focused on the overarching goal of increasing HIV testing among African American women in March 2012. We surveyed 200 members of the campaign?s priority audience to inform selection of updated concepts for the campaign. Two of the potential concepts (Love Yourself More and Look Out for Yourself) were updated versions of the original campaign concepts, and three (Control of My Life, Personal Potential, and Strong Sisters) were newly developed. Look Out for Yourself and Love Yourself More had the highest mean ratings on the perceived effectiveness scale (PES) and were not significantly different from each other. Control of My Life had the third highest mean rating on the PES and was not significantly different from Love Yourself More. All three concepts were rated significantly higher than Personal Potential and Strong Sisters (P?<?0.01). Across all concepts, prior intentions to get tested in the next 6 months was a positive, statistically significant predictor of the PES (P?<?0.001). Higher perceived effectiveness was significantly associated with agreement that the concept motivated the respondent to get tested for HIV across all five concepts (P?<?0.001). The findings support framing HIV testing as a matter of personal responsibility and emphasizing the importance of getting tested so that women can be there to participate in their children?s lives as effective messaging strategies for African American women.
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Data management and data quality in PERCH, a large international case-control study of severe childhood pneumoniaWatson NL, Prosperi C, Driscoll AJ, Higdon MM, Park DE, Sanza M, DeLuca AN, Awori JO, Goswami D, Hammond E, Hossain L, Johnson C, Kamau A, Kuwanda L, Moore DP, Neyzari O, Onwuchekwa U, Parker D,
Sapchookul P, Seidenberg P, Shamsul A, Siazeele K,
Srisaengchai P, Sylla M, Levine OS, Murdoch DR, O’Brien KL, Wolff M, Deloria Knoll M.
Clin Infect Dis. 2017 Jun 15;64(suppl_3):S238-s244.
The Pneumonia Etiology Research for Child Health (PERCH) study is the largest multicountry etiology study of pediatric pneumonia undertaken in the past 3 decades. The study enrolled 4232 hospitalized cases and 5325 controls over 2 years across 9 research sites in 7 countries in Africa and Asia. The volume and complexity of data collection in PERCH presented considerable logistical and technical challenges. The project chose an internet-based data entry system to allow real-time access to the data, enabling the project to monitor and clean incoming data and perform preliminary analyses throughout the study. To ensure high-quality data, the project developed comprehensive quality indicator, data query, and monitoring reports. Among the approximately 9000 cases and controls, analyzable laboratory results were available for >/=96% of core specimens collected. Selected approaches to data management in PERCH may be extended to the planning and organization of international studies of similar scope and complexity.
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Ebola virus disease contact tracing activities, lessons learned and best practices during the Duport Road outbreak in Monrovia, Liberia, November 2015Wolfe CM, Hamblion EL, Schulte J, Williams P, Koryon A, Enders J, Sanor V, Wapoe Y, Kwayon D,
Blackey D,
Laney AS,
Weston EJ,
Dokubo EK, Davies-Wayne G, Wendland A, Daw VT, Badini M, Clement P, Mahmoud N,
Williams D, Gasasira A, Nyenswah TG, Fallah M.
PLoS Negl Trop Dis. 2017 Jun 02;11(6):e0005597.
BACKGROUND: Contact tracing is one of the key response activities necessary for halting Ebola Virus Disease (EVD) transmission. Key elements of contact tracing include identification of persons who have been in contact with confirmed EVD cases and careful monitoring for EVD symptoms, but the details of implementation likely influence their effectiveness. In November 2015, several months after a major Ebola outbreak was controlled in Liberia, three members of a family were confirmed positive for EVD in the Duport Road area of Monrovia. The cluster provided an opportunity to implement and evaluate modified approaches to contact tracing. METHODS: The approaches employed for improved contact tracing included classification and risk-based management of identified contacts (including facility based isolation of some high risk contacts, provision of support to persons being monitored, and school-based surveillance for some persons with potential exposure but not listed as contacts), use of phone records to help locate missing contacts, and modifications to data management tools. We recorded details about the implementation of these approaches, report the overall outcomes of the contact tracing efforts and the challenges encountered, and provide recommendations for management of future outbreaks. RESULTS: 165 contacts were identified (with over 150 identified within 48 hours of confirmation of the EVD cases) and all initially missing contacts were located. Contacts were closely monitored and promptly tested if symptomatic; no contacts developed disease. Encountered challenges related to knowledge gaps among contact tracing staff, data management, and coordination of contact tracing activities with efforts to offer Ebola vaccine. CONCLUSIONS: The Duport Road EVD cluster was promptly controlled. Missing contacts were effectively identified, and identified contacts were effectively monitored and rapidly tested. There is a persistent risk of EVD reemergence in Liberia; the experience controlling each cluster can help inform future Ebola control efforts in Liberia and elsewhere.
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