Genomic analysis, immunomodulation and deep phenotyping of patients with nodding syndrome.

The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distinctive pattern of sleep-activated epileptiform activity. The associated growth stunting may be due to hypothalamic dysfunction. Extensive testing years after disease onset did not clarify a causal aetiology. A trial of immunomodulation (plasmapheresis in two patients and intravenous immunoglobulin in one patient) was given without short-term effect, but longer-term follow-up was not possible to fully assess any benefit of this intervention.

Toward Understanding Death.

Evidence-based approaches to preventing child death require evidence; without data on common causes of child mortality, taking effective action to prevent these deaths is difficult at best. Minimally invasive tissue sampling (MITS) is a potentially powerful, but nascent, technique to obtain gold standard information on causes of death. The Gates Foundation committed to further establishing the methodology and obtain the highest quality information on the major causes of death for children under 5 years. In 2018, the MITS Surveillance Alliance was launched to implement, refine, and enhance the use of MITS across high mortality settings. The Alliance and its members have contributed to some remarkable opportunities to improve mortality surveillance, and we have only just begun to understand the possibilities on larger scales. This supplement showcases studies conducted by MITS Surveillance Alliance members and represents a significant contribution to the cause-of-death literature from high mortality settings.

Why Child Health and Mortality Prevention Surveillance?

Recognizing the need for better primary data on the causes of global child mortality, the Bill & Melinda Gates Foundation made an unusually long funding commitment toward a surveillance system using pathology to identify opportunities to prevent child deaths and promote equity.

Infectious causes of encephalitis and meningoencephalitis in Thailand, 2003-2005.

Acute encephalitis is a severe neurologic syndrome. Determining etiology from among ≈100 possible agents is difficult. To identify infectious etiologies of encephalitis in Thailand, we conducted surveillance in 7 hospitals during July 2003-August 2005 and selected patients with acute onset of brain dysfunction with fever or hypothermia and with abnormalities seen on neuroimages or electroencephalograms or with cerebrospinal fluid pleocytosis. Blood and cerebrospinal fluid were tested for >30 pathogens. Among 149 case-patients, median age was 12 (range 0-83) years, 84 (56%) were male, and 15 (10%) died. Etiology was confirmed or probable for 54 (36%) and possible or unknown for 95 (64%). Among confirmed or probable etiologies, the leading pathogens were Japanese encephalitis virus, enteroviruses, and Orientia tsutsugamushi. No samples were positive for chikungunya, Nipah, or West Nile viruses; Bartonella henselae; or malaria parasites. Although a broad range of infectious agents was identified, the etiology of most cases remains unknown.

Rapidly building global health security capacity--Uganda demonstration project, 2013.

Increasingly, the need to strengthen global capacity to prevent, detect, and respond to public health threats around the globe is being recognized. CDC, in partnership with the World Health Organization (WHO), has committed to building capacity by assisting member states with strengthening their national capacity for integrated disease surveillance and response as required by International Health Regulations (IHR). CDC and other U.S. agencies have reinforced their pledge through creation of global health security (GHS) demonstration projects. One such project was conducted during March-September 2013, when the Uganda Ministry of Health (MoH) and CDC implemented upgrades in three areas: 1) strengthening the public health laboratory system by increasing the capacity of diagnostic and specimen referral networks, 2) enhancing the existing communications and information systems for outbreak response, and 3) developing a public health emergency operations center (EOC) (Figure 1). The GHS demonstration project outcomes included development of an outbreak response module that allowed reporting of suspected cases of illness caused by priority pathogens via short messaging service (SMS; i.e., text messaging) to the Uganda District Health Information System (DHIS-2) and expansion of the biologic specimen transport and laboratory reporting system supported by the President's Emergency Plan for AIDS Relief (PEPFAR). Other enhancements included strengthening laboratory management, establishing and equipping the EOC, and evaluating these enhancements during an outbreak exercise. In 6 months, the project demonstrated that targeted enhancements resulted in substantial improvements to the ability of Uganda's public health system to detect and respond to health threats.

Strengthening global health security capacity--Vietnam demonstration project, 2013.

Over the past decade, Vietnam has successfully responded to global health security (GHS) challenges, including domestic elimination of severe acute respiratory syndrome (SARS) and rapid public health responses to human infections with influenza A(H5N1) virus. However, new threats such as Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza A(H7N9) present continued challenges, reinforcing the need to improve the global capacity to prevent, detect, and respond to public health threats. In June 2012, Vietnam, along with many other nations, obtained a 2-year extension for meeting core surveillance and response requirements of the 2005 International Health Regulations (IHR). During March-September 2013, CDC and the Vietnamese Ministry of Health (MoH) collaborated on a GHS demonstration project to improve public health emergency detection and response capacity. The project aimed to demonstrate, in a short period, that enhancements to Vietnam's health system in surveillance and early detection of and response to diseases and outbreaks could contribute to meeting the IHR core capacities, consistent with the Asia Pacific Strategy for Emerging Diseases. Work focused on enhancements to three interrelated priority areas and included achievements in 1) establishing an emergency operations center (EOC) at the General Department of Preventive Medicine with training of personnel for public health emergency management; 2) improving the nationwide laboratory system, including enhanced testing capability for several priority pathogens (i.e., those in Vietnam most likely to contribute to public health emergencies of international concern); and 3) creating an emergency response information systems platform, including a demonstration of real-time reporting capability. Lessons learned included awareness that integrated functions within the health system for GHS require careful planning, stakeholder buy-in, and intradepartmental and interdepartmental coordination and communication.

Progress in global surveillance and response capacity 10 years after severe acute respiratory syndrome.

Ten years have elapsed since the World Health Organization issued its first global alert for an unexplained illness named severe acute respiratory syndrome (SARS). The anniversary provides an opportunity to reflect on the international response to this new global microbial threat. While global surveillance and response capacity for public health threats have been strengthened, critical gaps remain. Of 194 World Health Organization member states that signed on to the International Health Regulations (2005), <20% had achieved compliance with the core capacities required by the deadline in June 2012. Lessons learned from the global SARS outbreak highlight the need to avoid complacency, strengthen efforts to improve global capacity to address the next pandemic using all available 21st century tools, and support research to develop new treatment options, countermeasures, and insights while striving to address the global inequities that are the root cause of many of these challenges.

Nodding syndrome.

An epidemic illness characterized by head nodding associated with onchocerciasis has been described in eastern Africa since the early 1960s; we summarize published reports and recent studies. Onset of nodding occurs in previously healthy 5-15-year-old children and is often triggered by eating or cold temperatures and accompanied by cognitive impairment. Its incidence has increased in Uganda and South Sudan over the past 10 years. Four case-control studies identified modest and inconsistent associations. There were nonspecific lesions seen by magnetic resonance imaging, no cerebrospinal fluid inflammation, and markedly abnormal electroencephalography results. Nodding episodes are atonic seizures. Testing has failed to demonstrate associations with trypanosomiasis, cysticercosis, loiasis, lymphatic filariasis, cerebral malaria, measles, prion disease, or novel pathogens; or deficiencies of folate, cobalamin, pyridoxine, retinol, or zinc; or toxicity from mercury, copper, or homocysteine. There is a consistent enigmatic association with onchocerciasis detected by skin snip or serologic analysis. Nodding syndrome is an unexplained epidemic epilepsy.

Evaluation of the Global Health Security Index as a predictor of COVID-19 excess mortality standardised for under-reporting and age structure.

BACKGROUND: Previous studies have observed that countries with the strongest levels of pandemic preparedness capacities experience the greatest levels of COVID-19 burden. However, these analyses have been limited by cross-country differentials in surveillance system quality and demographics. Here, we address limitations of previous comparisons by exploring country-level relationships between pandemic preparedness measures and comparative mortality ratios (CMRs), a form of indirect age standardisation, of excess COVID-19 mortality. METHODS: We indirectly age standardised excess COVID-19 mortality, from the Institute for Health Metrics and Evaluation modelling database, by comparing observed total excess mortality to an expected age-specific COVID-19 mortality rate from a reference country to derive CMRs. We then linked CMRs with data on country-level measures of pandemic preparedness from the Global Health Security (GHS) Index. These data were used as input into multivariable linear regression analyses that included income as a covariate and adjusted for multiple comparisons. We conducted a sensitivity analysis using excess mortality estimates from WHO and The Economist. RESULTS: The GHS Index was negatively associated with excess COVID-19 CMRs (table 2; ß= -0.21, 95% CI= -0.35 to -0.08). Greater capacities related to prevention (ß= -0.11, 95% CI= -0.22 to -0.00), detection (ß= -0.09, 95% CI= -0.19 to -0.00), response (ß = -0.19, 95% CI= -0.36 to -0.01), international commitments (ß= -0.17, 95% CI= -0.33 to -0.01) and risk environments (ß= -0.30, 95% CI= -0.46 to -0.15) were each associated with lower CMRs. Results were not replicated using excess mortality models that rely more heavily on reported COVID-19 deaths (eg, WHO and The Economist). CONCLUSION: The first direct comparison of COVID-19 excess mortality rates across countries accounting for under-reporting and age structure confirms that greater levels of preparedness were associated with lower excess COVID-19 mortality. Additional research is needed to confirm these relationships as more robust national-level data on COVID-19 impact become available.

International Health Regulations--what gets measured gets done.

The global spread of severe acute respiratory syndrome highlighted the need to detect and control disease outbreaks at their source, as envisioned by the 2005 revised International Health Regulations (IHR). June 2012 marked the initial deadline by which all 194 World Health Organization (WHO) member states agreed to have IHR core capacities fully implemented for limiting the spread of public health emergencies of international concern. Many countries fell short of these implementation goals and requested a 2-year extension. The degree to which achieving IHR compliance will result in global health security is not clear, but what is clear is that progress against the threat of epidemic disease requires a focused approach that can be monitored and measured efficiently. We developed concrete goals and metrics for 4 of the 8 core capacities with other US government partners in consultation with WHO and national collaborators worldwide. The intent is to offer an example of an approach to implementing and monitoring IHR for consideration or adaptation by countries that complements other frameworks and goals of IHR. Without concrete metrics, IHR may waste its considerable promise as an instrument for global health security against public health emergencies.

Implications of the introduction of cholera to Haiti.

With more than 250,000 cases and 4,000 deaths in the first 6 months, the cholera epidemic in Haiti has been one of the most explosive and deadly in recent history. It is also one of the best documented, with detailed surveillance information available from the beginning of the epidemic, which allowed its spread to all parts of the country to be traced. Piarroux et al. make good use of this information, along with their own careful field investigations, to trace the epidemic to its beginning and propose an explanation for its origins.

Bartonella seroprevalence in rural Thailand.

We estimated the prevalence of anti-Bartonella antibodies among febrile and non-febrile patients presenting to community hospitals in rural Thailand from February 2002 through March 2003. Single serum specimens were tested for IgG titers to four Bartonella species, B. henselae, B. quintana, B. elizabethae and B. vinsonii subsp vinsonii using an indirect immunofluorescent assay. A titer 21:256 was considered positive. Forty-two febrile patients (9.9%) and 19 non-febrile patients (19%) had positive serology titers to at least one Bartonella species. Age-standardized Bartonella seroprevalence differed significantly between febrile (10%) and non-febrile patients (18%, p=0.047), but did not differ by gender. Among all 521 patients, IgG titers 21:256 to B. henselae were found in 20 participants (3.8%), while 17 (3.3%) had seropositivity to B. quintana, 51 (9.8%) to B. elizabethae, and 19 (3.6%) to B. vinsonii subsp vinsonii. These results suggest exposure to Bartonella species is more common in rural Thailand than previously suspected.

Influenza circulation and the burden of invasive pneumococcal pneumonia during a non-pandemic period in the United States.

BACKGROUND: Animal models and data from influenza pandemics suggest that influenza infection predisposes individuals to pneumococcal pneumonia. Influenza may contribute to high winter rates of pneumococcal pneumonia during non-pandemic periods, but the magnitude of this effect is unknown. With use of United States surveillance data during 1995-2006, we estimated the association between influenza circulation and invasive pneumococcal pneumonia rates. METHODS: Weekly invasive pneumococcal pneumonia incidence, defined by isolation of pneumococci from normally sterile sites in persons with clinical or radiographic pneumonia, was estimated from active population-based surveillance in 3 regions of the United States. We used influenza virus data collected by World Health Organization collaborating laboratories in the same 3 regions in seasonally adjusted negative binomial regression models to estimate the influenza-associated fraction of pneumococcal pneumonia. RESULTS: During approximately 185 million person-years of surveillance, we observed 21,239 episodes of invasive pneumococcal pneumonia; 485,691 specimens were tested for influenza. Influenza circulation was associated with 11%-14% of pneumococcal pneumonia during periods of influenza circulation and 5%-6% overall. In 2 of 3 regions, the association was strongest when influenza circulation data were lagged by 1 week. CONCLUSIONS: During recent seasonal influenza epidemics in the United States, a modest but potentially preventable fraction of invasive pneumococcal pneumonia was associated with influenza circulation.

Younger ages at risk of Covid-19 mortality in communities of color.

More than 85% of Covid-19 mortality in high income countries is among people 65 years of age or older. Recent disaggregated data from the UK and US show that minority communities have increased mortality among younger age groups and in South Africa initial data suggest that the majority of deaths from Covid-19 are under 65 years of age. These observations suggest significant potential for increased Covid-19 mortality among younger populations in Africa and South Asia and may impact age-based selection of high-risk groups eligible for a future vaccine.

Initial findings from a novel population-based child mortality surveillance approach: a descriptive study.

BACKGROUND: Sub-Saharan Africa and south Asia contributed 81% of 5·9 million under-5 deaths and 77% of 2·6 million stillbirths worldwide in 2015. Vital registration and verbal autopsy data are mainstays for the estimation of leading causes of death, but both are non-specific and focus on a single underlying cause. We aimed to provide granular data on the contributory causes of death in stillborn fetuses and in deceased neonates and children younger than 5 years, to inform child mortality prevention efforts. METHODS: The Child Health and Mortality Prevention Surveillance (CHAMPS) Network was established at sites in seven countries (Baliakandi, Bangladesh; Harar and Kersa, Ethiopia; Siaya and Kisumu, Kenya; Bamako, Mali; Manhiça, Mozambique; Bombali, Sierra Leone; and Soweto, South Africa) to collect standardised, population-based, longitudinal data on under-5 mortality and stillbirths in sub-Saharan Africa and south Asia, to improve the accuracy of determining causes of death. Here, we analysed data obtained in the first 2 years after the implementation of CHAMPS at the first five operational sites, during which surveillance and post-mortem diagnostics, including minimally invasive tissue sampling (MITS), were used. Data were abstracted from all available clinical records of deceased children, and relevant maternal health records were also extracted for stillbirths and neonatal deaths, to incorporate reported pregnancy or delivery complications. Expert panels followed standardised procedures to characterise causal chains leading to death, including underlying, intermediate (comorbid or antecedent causes), and immediate causes of death for stillbirths, neonatal deaths, and child (age 1-59 months) deaths. FINDINGS: Between Dec 10, 2016, and Dec 31, 2018, MITS procedures were implemented at five sites in Mozambique, South Africa, Kenya, Mali, and Bangladesh. We screened 2385 death notifications for inclusion eligibility, following which 1295 families were approached for consent; consent was provided for MITS by 963 (74%) of 1295 eligible cases approached. At least one cause of death was identified in 912 (98%) of 933 cases (180 stillbirths, 449 neonatal deaths, and 304 child deaths); two or more conditions were identified in the causal chain for 585 (63%) of 933 cases. The most common underlying causes of stillbirth were perinatal asphyxia or hypoxia (130 [72%] of 180 stillbirths) and congenital infection or sepsis (27 [15%]). The most common underlying causes of neonatal death were preterm birth complications (187 [42%] of 449 neonatal deaths), perinatal asphyxia or hypoxia (98 [22%]), and neonatal sepsis (50 [11%]). The most common underlying causes of child deaths were congenital birth defects (39 [13%] of 304 deaths), lower respiratory infection (37 [12%]), and HIV (35 [12%]). In 503 (54%) of 933 cases, at least one contributory pathogen was identified. Cytomegalovirus, Escherichia coli, group B Streptococcus, and other infections contributed to 30 (17%) of 180 stillbirths. Among neonatal deaths with underlying prematurity, 60% were precipitated by other infectious causes. Of the 275 child deaths with infectious causes, the most common contributory pathogens were Klebsiella pneumoniae (86 [31%]), Streptococcus pneumoniae (54 [20%]), HIV (40 [15%]), and cytomegalovirus (34 [12%]), and multiple infections were common. Lower respiratory tract infection contributed to 174 (57%) of 304 child deaths. INTERPRETATION: Cause of death determination using MITS enabled detailed characterisation of contributing conditions. Global estimates of child mortality aetiologies, which are currently based on a single syndromic cause for each death, will be strengthened by findings from CHAMPS. This approach adds specificity and provides a more complete overview of the chain of events leading to death, highlighting multiple potential interventions to prevent under-5 mortality and stillbirths. FUNDING: Bill & Melinda Gates Foundation.

Incidence of pneumococcal bacteremia requiring hospitalization in rural Thailand.

BACKGROUND: Population-based estimates of the incidence of invasive pneumococcal disease are unavailable for Thailand and other countries in Southeast Asia. We estimated the incidence of pneumococcal bacteremia cases requiring hospitalization in rural Thailand. METHODS: Blood cultures were performed on samples from hospitalized patients in 2 rural provinces where active, population-based surveillance of community-acquired pneumonia is conducted. Blood cultures were performed at clinician discretion and were encouraged for all patients with suspected pneumonia and all children aged <5 years with suspected sepsis. Pneumococcal antigen testing was performed on positive blood culture specimens that failed to grow organisms on subculture. RESULTS: From May 2005 through June 2007, 23,853 blood culture specimens were collected overall, and 7319 were collected from children aged <5 years, which represented 66% and 47% of target patients, respectively. A total of 72 culture-confirmed pneumococcal bacteremia cases requiring hospitalization were identified. An additional 44 patients had media from positive blood cultures that yielded no growth on subculture but that had positive results of pneumococcal antigen testing. Of the 116 confirmed cases of bacteremia, 27 (23%) occurred in children aged <5 years; of these, 9 (33%) were confirmed by antigen testing only. The incidence of pneumococcal bacteremia cases requiring hospitalization among children aged <5 years had a range of 10.6-28.9 cases per 100,000 persons (incidence range if cases detected by antigen are excluded, 7.5-14.0 cases per 100,000 persons). CONCLUSIONS: Invasive pneumococcal disease is more common than was previously suspected in Thailand, even on the basis of estimates limited to hospitalized cases of bacteremia. These estimates, which are close to estimates of the incidence of hospitalized cases of pneumococcal bacteremia in the United States before introduction of pneumococcal conjugate vaccine, provide important data to guide public health care policy and to inform discussions about vaccine introduction in Thailand and the rest of Southeast Asia.