BACKGROUND: In resource-limited settings, acute respiratory infections continue to be the leading cause of death in young children. We conducted postmortem investigations in children <5 years hospitalized with a clinical diagnosis of respiratory disease at Kenya's largest referral hospital. METHODS: We collected respiratory and other tissues postmortem to examine pathologic processes using histology, molecular and immunohistochemistry assays. Nasopharyngeal, trachea, bronchi and lung specimens were tested using 21-target respiratory pathogen real-time reverse transcription polymerase chain reaction assays deployed on Taqman Array Cards. Expert panels reviewed all findings to determine causes of death and associated pathogens. RESULTS: From 2014 to 2015, we investigated 64 pediatric deaths (median age 7 months). Pneumonia was determined as cause of death in 70% (42/52) of cases where death was associated with an infectious disease process. The main etiologies of pneumonia deaths were respiratory syncytial virus (RSV) (n = 7, 19%), Pneumocystis jirovecii (n = 7, 19%), influenza A (n = 5, 14%) and Streptococcus pneumoniae (n = 5, 14%)-10% of cases had multi-pathogen involvement. Among the other 10 deaths associated with a nonpneumonia infectious process, 4 did not have an etiology assigned, the others were associated with miliary tuberculosis (2), cerebral thrombosis due to HIV (1), Enterobacteriaceae (1), rotavirus (1), and 1 case of respiratory infection with severe hypokalemia associated with RSV. CONCLUSIONS: In spite of well-established vaccination programs in Kenya, some deaths were still vaccine preventable. Accelerated development of RSV monoclonal antibodies and vaccines, introduction of seasonal influenza vaccination, and maintenance or improved uptake of existing vaccines can contribute to further reductions in childhood mortality.

Maternal and neonatal tetanus* (MNT) remains a major public health problem, with an 80%-100% case-fatality rate among neonates, especially in areas with poor immunization coverage and limited access to clean deliveries (i.e., delivery in a health facility or assisted by medically trained attendants in sanitary conditions) and umbilical cord care (1). In 1989, the World Health Assembly endorsed the elimination(dagger) of neonatal tetanus (NT), and in 1999, the initiative was relaunched and renamed the MNT elimination( section sign) initiative, targeting 59( paragraph sign) priority countries (1). Elimination strategies include 1) achieving >/=80% coverage with >/=2 doses of tetanus toxoid-containing vaccine (TTCV) among women of reproductive age through routine immunization of pregnant women and supplementary immunization activities (SIAs)** in high-risk areas and districts(daggerdagger); 2) achieving care at >/=70% of deliveries by a skilled birth attendant (SBA)( section sign section sign); and 3) enhancing surveillance for NT cases (1). This report summarizes progress toward achieving MNT elimination during 2000-2018. Coverage with >/=2 doses of TTCV (2 doses of tetanus toxoid [TT2+] or 2 doses of tetanus-diphtheria toxoid [Td2+]) among women of reproductive age increased by 16%, from 62% in 2000 to 72% in 2018. By December 2018, 52 (88%) of 59 priority countries had conducted TTCV SIAs, vaccinating 154 million (77%) of 201 million targeted women of reproductive age with TT2+/Td2+. Globally, the percentage of deliveries assisted by SBAs increased from 62% during 2000-2005 to 81% during 2013-2018, and estimated neonatal tetanus deaths decreased by 85%, from 170,829 in 2000 to 25,000 in 2018. By December 2018, 45 (76%) of 59 priority countries were validated by WHO as having achieved MNT elimination. To achieve elimination in the remaining 14 countries and sustain elimination in countries that have achieved it, implementation of MNT elimination strategies needs to be maintained and strengthened, and TTCV booster doses need to be included in country immunization schedules as recommended by the World Health Organization (WHO) (2). In addition, integration of maternal, newborn, and child health services with vaccination services is needed, as well as innovative approaches to target hard-to-reach areas for tetanus vaccination and community engagement to strengthen surveillance.

Molecular diagnostic methods are becoming increasingly available for assessment of acute lower respiratory illnesses (ALRI). However, nasopharyngeal/oropharyngeal (NP/OP) swabs may not accurately reflect etiologic agents from the lower respiratory tract where sputum specimens are considered as a more representative sample. The pathogen yields from NP/OP against sputum specimens have not been extensively explored, especially in tropical countries. We compared pathogen yields from NP/OP swabs and sputum specimens from patients ≥18 years hospitalized with ALRI in rural Western Kenya. Specimens were tested for 30 pathogens using TaqMan Array Cards (TAC) and results compared using McNemar’s test. The agreement for pathogen detection between NP/OP and sputum specimens ranged between 85–100%. More viruses were detected from NP/OP specimens whereas Klebsiella pneumoniae and Mycobacterium tuberculosis were more common in sputum specimens. There was no clear advantage in using sputum over NP/OP specimens to detect pathogens of ALRI in adults using TAC in the context of this tropical setting.

BACKGROUND: Clinical autopsies are not often part of routine care, despite their role in clarifying cause of death. In fact, autopsy rates across the world have declined and are especially low in sub-Saharan Africa. OBJECTIVES: We set out to identify factors associated with acceptance of pediatric autopsies among parents of deceased children less than five years old, and examined local preferences for minimally invasive tissue sampling (MITS) procedures during post-mortem (PM) examinations. METHODS: From December 2016 to September 2017, we contacted 113 parents/next of kin who had been previously approached to consent to a PM examination of their deceased child as part of a Kenyan study on cause of death. Interviews occurred up to three years after the death of their child. FINDINGS: Seventy-three percent (83/113) of eligible study participants were enrolled, of whom 62/83 (75%) had previously consented to PM examination of their child. Those who previously consented to PM had higher levels of education, were more likely employed, and had more knowledge about certain aspects of autopsies than non-consenters. The majority (97%) of PM consenters did so because they wanted to know the cause of death of their child, and up to a third believed autopsy studies helped advance medical knowledge. Reasons for non-consent to PM examination included: parents felt there was no need for further examination (29%) or they were satisfied with the clinical diagnosis (24%). Overall, only 40% of study participants would have preferred MITS procedures to conventional autopsy. However, 81% of autopsy non-consenters would have accepted PM examination if it only involved MITS techniques. CONCLUSION: There is potential to increase autopsy rates by strengthening reasons for acceptance and addressing modifiable reasons for refusals. Although MITS procedures have the potential to improve autopsy acceptance rates, they were not significantly preferred over conventional autopsies in our study population.

During January 22-March 23, 2018, a local health department in Washington was notified of two patients who received a diagnosis of acute hepatitis C virus (HCV) infection. Neither patient had behavioral risk factors associated with HCV acquisition; however, both had received injectable narcotic (opioid) drugs from the same nurse during separate visits to an emergency department (ED) at a local hospital on December 6 and December 16, 2017. Investigation revealed that the nurse had accessed the automated drug dispensing system at a higher frequency than had other staff members, admitted diverting* patients' injectable narcotic and antihistamine drugs for personal use, and tested positive for HCV antibodies (anti-HCV) on March 19, 2018, but did not have quantifiable HCV RNA. Specimens from both patients were sent to CDC for genetic testing, and HCV viral variants analysis found a significant level of genetically similar HCV variants in both patients, indicating a common source of infection. Further investigation was conducted to confirm the infection source, identify other potentially exposed patients, and treat any new patients who received an HCV diagnosis. Monitoring frequency of access to drug dispensing systems can help identify staff members with abnormal dispensing patterns, including diversion activities (1). U.S. health care facilities are required to prevent, identify, and report any loss, diversion, or theft of controlled substances (2).

OBJECTIVES: We compared minimally invasive tissue sampling (MITS) with conventional autopsy (CA) in detection of respiratory pathology/pathogens among Kenyan children younger than 5 years who were hospitalized with respiratory disease and died during hospitalization. METHODS: Pulmonary MITS guided by anatomic landmarks was followed by CA. Lung tissues were triaged for histology and molecular testing using TaqMan Array Cards (TACs). MITS and CA results were compared for adequacy and concordance. RESULTS: Adequate pulmonary tissue was obtained by MITS from 54 (84%) of 64 respiratory deaths. Comparing MITS to CA, full histologic diagnostic concordance was present in 23 (36%) cases and partial concordance in 19 (30%), an overall 66% concordance rate. Pathogen detection using TACs had full concordance in 27 (42%) and partial concordance in 24 (38%) cases investigated, an overall 80% concordance rate. CONCLUSIONS: MITS is a viable alternative to CA in respiratory deaths in resource-limited settings, especially if combined with ancillary tests to optimize diagnostic accuracy.

BACKGROUND: In sub-Saharan Africa, where the burden of respiratory disease-related deaths is the highest, information on the cause of death remains inadequate because of poor access to health care and limited availability of diagnostic tools. Postmortem examination can aid in the ascertainment of causes of death. This manuscript describes the study protocol for the Pediatric Respiratory Etiology Surveillance Study (PRESS). OBJECTIVE: This study protocol aims to identify causes and etiologies associated with respiratory disease-related deaths among children (age 1-59 months) with respiratory illness admitted to the Kenyatta National Hospital (KNH), the largest public hospital in Kenya, through postmortem examination coupled with innovative approaches to laboratory investigation. METHODS: We prospectively followed children hospitalized with respiratory illness until the end of clinical care or death. In case of death, parents or guardians were offered grief counseling, and postmortem examination was offered. Lung tissue specimens were collected using minimally invasive tissue sampling and conventional autopsy where other tissues were collected. Tissues were tested using histopathology, immunohistochemistry, and multipathogen molecular-based assays to identify pathogens. For each case, clinical and laboratory data were reviewed by a team of pathologists, clinicians, laboratorians, and epidemiologists to assign a cause of and etiology associated with death. RESULTS: We have enrolled pediatric cases of respiratory illness hospitalized at the KNH at the time of this submission; of those, 14.8% (140/945) died while in the hospital. Both analysis and interpretation of laboratory results and writing up of findings are expected in 2019-2020. CONCLUSIONS: Postmortem studies can help identify major pathogens contributing to respiratory-associated deaths in children. This information is needed to develop evidence-based prevention and treatment policies that target important causes of pediatric respiratory mortality and assist with the prioritization of local resources. Furthermore, PRESS can provide insights into the interpretation of results using multipathogen testing platforms in resource-limited settings. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/10854.

BACKGROUND: Influenza-associated respiratory illness was substantial during the emergence of the 2009 influenza pandemic. Estimates of influenza burden in the post-pandemic period are unavailable to guide Kenyan vaccine policy. OBJECTIVES: To update estimates of hospitalized and non-hospitalized influenza-associated severe acute respiratory illness (SARI) during a post-pandemic period (2012-2014) and describe the incidence of disease by narrow age categories. METHODS: We used data from Siaya County Referral Hospital to estimate age-specific base rates of SARI. We extrapolated these base rates to other regions within the country by adjusting for regional risk factors for acute respiratory illness (ARI), regional healthcare utilization for acute respiratory illness, and the proportion of influenza-positive SARI cases in each region, so as to obtain region-specific rates. RESULTS: The mean annual rate of hospitalized influenza-associated SARI among all ages was 21 (95% CI 19-23) per 100 000 persons. Rates of non-hospitalized influenza-associated SARI were approximately 4 times higher at 82 (95% CI 74-90) per 100 000 persons. Mean annual rates of influenza-associated SARI were highest in children <2 years of age with annual hospitalization rates of 147 (95% CI of 134-160) per 100 000 persons and non-hospitalization rates of 469 (95% CI 426-517) per 100 000 persons. For the period 2012-2014, there were between 8153 and 9751 cases of hospitalized influenza-associated SARI and 31 785-38 546 cases of non-hospitalized influenza-associated SARI per year. CONCLUSIONS: The highest burden of disease was observed among children <2 years of age. This highlights the need for strategies to prevent influenza infections in this age group.

BACKGROUND: Respiratory diseases cause substantial morbidity and mortality worldwide, with sub-Saharan Africa bearing the greatest burden. Identifying etiologies of respiratory disease is important to inform cost effective treatment, prevention and control strategies. Testing for all of the different pathogens that are potentially associated with respiratory illnesses is challenging. We piloted the use of a multi-pathogen respiratory Taqman Array Cards (TAC) to identify pathogens in respiratory samples collected from non-fatal and fatal cases and their matched asymptomatic controls. METHODS: This is a case control study comparing viral and bacterial pathogens detected among non-fatal and fatal cases to those detected among age and time matched asymptomatic controls. We used McNemar's test to compare proportions of pathogens detected among cases (non-fatal and fatal) to their matched asymptomatic controls. We used Mann-Whitney test to compare the distribution of median Cycle threshold (Ct) values among non-fatal and fatal cases to their corresponding asymptomatic controls. RESULTS: There were 72 fatal and 72 non-fatal cases matched to 72 controls. We identified at least one pathogen in 109/144 (76%) cases and 59/72 (82%) controls. For most pathogens, the median Ct values were lower among cases (fatal and non-fatal) compared to asymptomatic controls. CONCLUSIONS: Similar rates of pathogen detection among cases and controls make interpretation of results challenging. Ct-values might be helpful in interpreting clinical relevance of detected pathogens using multi-pathogen diagnostic tools.

BACKGROUND: In order to better understand respiratory syncytial virus (RSV) epidemiology and burden in tropical Africa, optimal case definitions for detection of RSV cases need to be identified. METHODS: We used data collected between September 2009 - August 2013 from children aged <5 years hospitalized with acute respiratory Illness at Siaya County Referral Hospital. We evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of individual signs, symptoms and standard respiratory disease case definitions (severe acute respiratory illness [SARI]; hospitalized influenza-like illness [hILI]; integrated management of childhood illness [IMCI] pneumonia) to detect laboratory-confirmed RSV infection. We also evaluated an alternative case definition of cough or difficulty breathing plus hypoxia, in-drawing, or wheeze. RESULTS: Among 4714 children hospitalized with ARI, 3810 (81 %) were tested for RSV; and 470 (12 %) were positive. Among individual signs and symptoms, cough alone had the highest sensitivity to detect laboratory-confirmed RSV [96 %, 95 % CI (95-98)]. Hypoxia, wheezing, stridor, nasal flaring and chest wall in-drawing had sensitivities ranging from 8 to 31 %, but had specificities >75 %. Of the standard respiratory case definitions, SARI had the highest sensitivity [83 %, 95 % CI (79-86)] whereas IMCI severe pneumonia had the highest specificity [91 %, 95 % CI (90-92)]. The alternative case definition (cough or difficulty breathing plus hypoxia, in-drawing, or wheeze) had a sensitivity of [55 %, 95 % CI (50-59)] and a specificity of [60 %, 95 % CI (59-62)]. The PPV for all case definitions and individual signs/symptoms ranged from 11 to 20 % while the negative predictive values were >87 %. When we stratified by age <1 year and 1- < 5 years, difficulty breathing, severe pneumonia and the alternative case definition were more sensitive in children aged <1 year [70 % vs. 54 %, p < 0.01], [19 % vs. 11 %, p = 0.01] and [66 % vs. 43 %, p < 0.01] respectively, while non-severe pneumonia was more sensitive [14 % vs. 26 %, p < 0.01] among children aged 1- < 5 years. CONCLUSION: The sensitivity and specificity of different commonly used case definitions for detecting laboratory-confirmed RSV cases varied widely, while the positive predictive value was consistently low. Optimal choice of case definition will depend upon study context and research objectives.

Although the severe acute respiratory illness (SARI) case definition is increasingly used for inpatient influenza surveillance, pneumonia is a more familiar term to clinicians and policymakers. We evaluated WHO case definitions for severe acute respiratory illness (SARI) and pneumonia (Integrated Management of Childhood Illnesses (IMCI) for children aged <5 years and Integrated Management of Adolescent and Adult Illnesses (IMAI) for patients aged ≥13 years) for detecting laboratory-confirmed influenza among hospitalized ARI patients. Sensitivities were 84% for SARI and 69% for IMCI pneumonia in children aged <5 years and 60% for SARI and 57% for IMAI pneumonia in patients aged ≥13 years. Clinical pneumonia case definitions may be a useful complement to SARI for inpatient influenza surveillance.

Nairobi is considered a low-risk area for malaria transmission, but travel can influence transmission of malaria. We investigated the demographic characteristics and travel history of patients with documented fever and malaria in a study clinic in a population-based surveillance system over a 5-year period, January 1, 2007 to December 31, 2011. During the study period, 11,480 (68%) febrile patients had a microscopy test performed for malaria, of which 2,553 (22%) were positive. Malaria was detected year-round with peaks in January, May, and September. Children aged 5-14 years had the highest proportion (28%) of positive results followed by children aged 1-4 years (23%). Almost two-thirds of patients with malaria reported traveling outside Nairobi; 79% of these traveled to three counties in western Kenya. History of recent travel (i.e., in past month) was associated with malaria parasitemia (odds ratio: 10.0, 95% confidence interval: 9.0-11.0). Malaria parasitemia was frequently observed among febrile patients at a health facility in the urban slum of Kibera, Nairobi. The majority of patients had traveled to western Kenya. However, 34% reported no travel history, which raises the possibility of local malaria transmission in this densely populated, urban setting. These findings have important implications for malaria control in large Nairobi settlements.

Influenza-associated disease burden among children in tropical sub-Saharan Africa is not well established, particularly outside of the 2009 pandemic period. We estimated the burden of influenza in children aged 0-4 years through population-based surveillance for influenza-like illness (ILI) and acute lower respiratory tract illness (ALRI). Household members meeting ILI or ALRI case definitions were referred to health facilities for evaluation and collection of nasopharyngeal and oropharyngeal swabs for influenza testing by real-time reverse transcription polymerase chain reaction. Estimates were adjusted for health-seeking behavior and those with ILI and ALRI who were not tested. During 2008-2012, there were 9,652 person-years of surveillance among children aged 0-4 years. The average adjusted rate of influenza-associated hospitalization was 4.3 (95% CI 3.0-6.0) per 1,000 person-years in children aged 0-4 years. Hospitalization rates were highest in the 0-5 month and 6-23 month age groups, at 7.6 (95% CI 3.2-18.2) and 8.4 (95% CI 5.4-13.0) per 1,000 person-years, respectively. The average adjusted rate of influenza-associated medically attended (inpatient or outpatient) ALRI in children aged 0-4 years was 17.4 (95% CI 14.2-19.7) per 1,000 person-years. Few children who had severe laboratory-confirmed influenza were clinically diagnosed with influenza by the treating clinician in the inpatient (0/33, 0%) or outpatient (1/109, 0.9%) settings. Influenza-associated hospitalization rates from 2008-2012 were 5-10 times higher than contemporaneous U.S. estimates. Many children with danger signs were not hospitalized; thus, influenza-associated severe disease rates in Kenyan children are likely higher than hospital-based estimates suggest.

BACKGROUND: Pediatric respiratory disease is a major cause of morbidity and mortality in the developing world. We evaluated a modified respiratory index of severity in children (mRISC) scoring system as a standard tool to identify children at greater risk of death from respiratory illness in Kenya. MATERIALS AND METHODS: We analyzed data from children <5 years old who were hospitalized with respiratory illness at Siaya District Hospital from 2009-2012. We used a multivariable logistic regression model to identify patient characteristics predictive for in-hospital mortality. Model discrimination was evaluated using the concordance statistic. Using bootstrap samples, we re-estimated the coefficients and the optimism of the model. The mRISC score for each child was developed by adding up the points assigned to each factor associated with mortality based on the coefficients in the multivariable model. RESULTS: We analyzed data from 3,581 children hospitalized with respiratory illness; including 218 (6%) who died. Low weight-for-age [adjusted odds ratio (aOR) = 2.1; 95% CI 1.3-3.2], very low weight-for-age (aOR = 3.8; 95% CI 2.7-5.4), caretaker-reported history of unconsciousness (aOR = 2.3; 95% CI 1.6-3.4), inability to drink or breastfeed (aOR = 1.8; 95% CI 1.2-2.8), chest wall in-drawing (aOR = 2.2; 95% CI 1.5-3.1), and being not fully conscious on physical exam (aOR = 8.0; 95% CI 5.1-12.6) were independently associated with mortality. The positive predictive value for mortality increased with increasing mRISC scores. CONCLUSIONS: A modified RISC scoring system based on a set of easily measurable clinical features at admission was able to identify children at greater risk of death from respiratory illness in Kenya.

BACKGROUND: Worldwide, Shigella causes an estimated 160 million infections and >1 million deaths annually. However, limited incidence data are available from African urban slums. We investigated the epidemiology of shigellosis and drug susceptibility patterns within a densely populated urban settlement in Nairobi, Kenya through population-based surveillance. METHODS: Surveillance participants were interviewed in their homes every 2 weeks by community interviewers. Participants also had free access to a designated study clinic in the surveillance area where stool specimens were collected from patients with diarrhea (≥3 loose stools within 24 hours) or dysentery (≥1 stool with visible blood during previous 24 hours). We adjusted crude incidence rates for participants meeting stool collection criteria at household visits who reported visiting another clinic. RESULTS: RShigella species were isolated from 224 (23%) of 976 stool specimens. The overall adjusted incidence rate was 408/100,000 person years of observation (PYO) with highest rates among adults 34-49 years old (1,575/100,000 PYO). Isolates were: Shigella flexneri (64%), S. dysenteriae (11%), S. sonnei (9%), and S. boydii (5%). Over 90% of all Shigella isolates were resistant to trimethoprim-sulfamethoxazole and sulfisoxazole. Additional resistance included nalidixic acid (3%), ciprofloxacin (1%) and ceftriaxone (1%). CONCLUSION: More than 1 of every 200 persons experience shigellosis each year in this Kenyan urban slum, yielding rates similar to those in some Asian countries. Provision of safe drinking water, improved sanitation, and hygiene in urban slums are needed to reduce disease burden, in addition to development of effective Shigella vaccines.

BACKGROUND: The epidemiology and burden of influenza remain poorly defined in sub-Saharan Africa. Since 2005, the Kenya Medical Research Institute and Centers for Disease Control and Prevention-Kenya have conducted population-based infectious disease surveillance in Kibera, an urban informal settlement in Nairobi, and in Lwak, a rural community in western Kenya. METHODS: Nasopharyngeal and oropharyngeal swab specimens were obtained from patients who attended the study clinic and had acute lower respiratory tract (LRT) illness. Specimens were tested for influenza virus by real-time reverse-transcription polymerase chain reaction. We adjusted the incidence of influenza-associated acute LRT illness to account for patients with acute LRT illness who attended the clinic but were not sampled. RESULTS: From March 2007 through February 2010, 4140 cases of acute LRT illness were evaluated in Kibera, and specimens were collected from 1197 (27%); 319 (27%) were positive for influenza virus. In Lwak, there were 6733 cases of acute LRT illness, and specimens were collected from 1641 (24%); 359 (22%) were positive for influenza virus. The crude and adjusted rates of medically attended influenza-associated acute LRT illness were 6.9 and 13.6 cases per 1000 person-years, respectively, in Kibera, and 5.6 and 23.0 cases per 1000 person-years, respectively, in Lwak. In both sites, rates of influenza-associated acute LRT illness were highest among children <2 years old and lowest among adults ≥50 years old. CONCLUSION: In Kenya, the incidence of influenza-associated acute LRT illness was high in both rural and urban settings, particularly among the most vulnerable age groups.