Understanding different opportunities to prevent severe disease and reduce mortality in African infants and children: From vertical transmission prevention to enhanced diagnosis of life-threatening conditions of childhood = Oportunidades para prevenir enfermedades graves y reducir la mortalidad en lactantes y niños africanos. Prevención de la transmisión vertical y mejora del diagnóstico de enfermedades que amenazan la vida de los niños

Abstract

Infant and child mortality have played a crucial role in health transition patterns and both have been considered as good indicators of development and demographic modernization. The establishment of the Millennium Development Goals (MDGs) meant a significant injection of funds and resources for health, and a national and international commitment to child health, which led to an unprecedented progress in the reduction of child mortality worldwide.

In terms of neonatal infections, neonatal sepsis and meningitis are well- known leading causes of mortality and severe sequelae in term and preterm babies in industrialized countries but information about them and their burden in LIC is more limited. Early-onset disease (EOD, 0-6 days), is usually vertically transmitted, and mainly caused by Group B streptococcus (GBS) and Escherichia coli (E. coli). Late-onset disease (LOD, 7-89 days) is generally due to horizontal infections (either community-acquired or hospital-acquired) and most frequently associated pathogens include E. coli, Klebsiella spp, GBS and other Gram-positive organisms (Staphylococcus aureus and Coagulase-negative staphylococci). Maternal colonization by these pathogens is crucial for transmission from mother to child to occur, presenting in such cases generally as EOD. Prevalence of maternal colonization may be affected by Human Immunodeficiency Virus (HIV), maternal nutritional status and other maternal risk factors. Prevention strategies such as maternal screening of GBS at the end of the pregnancy and intrapartum antibiotic prophylaxis (IAP) for those mothers found to be carriers have demonstrated their efficacy in dramatically reducing EOD. However, IAP as we know it is not currently reaching all women in need in poor settings, possibly in relation to the fragility of health systems, precariousness of laboratory infrastructures, or more simply because a significant proportion of deliveries in these settings still occurs at home. In addition, other preventive strategies against E. coli or those bacterial causing LOD have yet to be developed.

Other infectious diseases also considered as important contributors to neonatal, infant and even child morbidity and mortality include infections encompassed under the TORCH syndrome. The HIV pandemic and the Zika virus outbreak have raised great concern across the world and have highlighted the importance of other pathogens for infants, including viruses, parasites or fungi. Screening of some of these diseases such as syphilis or HIV is routinely offered to women attending antenatal care (ANC) clinics of LIC. However, further screening of other potential vertically transmitted pathogens, such as cytomegalovirus (CMV), rubella, toxoplasma gondii (T. gondii), enterovirus (EV), parvovirus B19 (B19V), herpes simplex virus (HSV) or hepatitis B virus (HBV), among others is not offered. Congenital CMV infection (cCMV) is the most prevalent and principal cause of deafness in developed countries. However, and similarly to other congenital infections, it remains fundamentally unnoticed and therefore largely neglected in resource-constrained settings, thus also hindering the characterization of its real burden and impact in these settings.

An interesting approach to prevent many of these congenital and neonatal infections now includes maternal vaccination during pregnancy under the assumption that maternal transfer of antibodies to the newborn will be more feasible, effective and rapidly protective than waiting for the generation of neonatal immune responses to vaccines administered directly to them. This “vertical vaccination” strategy has already been successfully implemented for tetanus and pertussis control, and is being explored against other pathogens.

There are other well-known causes of severe disease and mortality in children, although not usually listed as direct CoD and therefore often forgotten in global estimates. Malnourished children, neonates born with a low weight or small for their gestational age, may be prone to suffering life-threating conditions or developing significant sequelae. In many cases, the fatal outcome is determined by the underlying condition rather than the acute disease. On the other hand, the emergence of certain complications such as for instance hypoglycaemia, relatively common in the evolution of many different diseases or conditions (malaria, sepsis, diarrhoea cases, malnutrition or neonates in general), may also adversely determine the prognosis of these cases, although the real incidence and significance of such complications remains to be described and addressed as part of their management strategies.

In many LMIC, at least half the child deaths occur at home, often without having been seen by a clinician. In some cases, though, deaths occur also at home, but soon after a contact with the health system. Inpatient mortality is a well-understood portion of the global overall child mortality estimates, and interventions to reduce it have been developed and successfully implemented. However, post-discharge mortality (PDM) could be as high as inpatient mortality in those constrained-resource settings, but is clearly a neglected and understudied phenomenon. Indeed, no guidelines, recommendations or further strategies have been developed to address the care of patients during the days immediately following discharge, a critical period for child survival. The fragility of the health systems and scarcity of the health force in LIC, the unaffordable high costs to provide care for acute illness and the generalised lack of awareness about the burden and implications of PDM by health workers and policy makers partly explain this neglect.

This thesis aims to address issues related with those severe diseases that cause the majority of morbidity and deaths among neonates, infants and children under five and for which no specific interventions have yet been implemented. Most of the studies conforming this thesis have been conducted in Manhiça, a semi-rural area in Southern Mozambique, and a paradigmatic example of a resource-constrained setting.

La mortalidad de lactantes y niños ha jugado un papel crucial en los patrones de transición de la salud y es considerado un buen indicador de desarrollo y modernización demográfica a lo largo del tiempo. El establecimiento de los Objetivos de Desarrollo del Milenio (MDGs) supuso una importante inyección de fondos y recursos para la mejora de la salud y un compromiso nacional e internacional con la salud infantil, que condujo a un progreso sin precedentes en la reducción de la mortalidad infantil en todo el mundo.

En términos de infecciones neonatales, la sepsis neonatal y la meningitis son bien conocidas causas de muerte y enfermedades que pueden producir secuelas graves tanto en los bebés prematuros y como aquello a término en países industrializados. Sin embargo, la información sobre estas enfermedades y su impacto en los países empobrecidos del África subsahariana es más limitada.

Otras enfermedades infecciosas también consideradas como contribuyentes importantes a la morbi-mortalidad neonatal, del lactante e incluso de niños más mayores son las infecciones englobadas en el síndrome TORCH. La pandemia del VIH y el brote del virus del Zika han suscitado gran preocupación en todo el mundo y han destacado la importancia de otros patógenos que afectan a los niños incluyendo virus, parásitos y hongos. La detección de algunas de estas enfermedades, como la sífilis o el VIH, se ofrece de forma rutinaria a las mujeres atendidas en las consultas prenatales (ANC) de países empobrecidos. Sin embargo, no ocurre lo mismo con la detección de otros posibles patógenos potencialmente transmisibles al feto durante el embarazo y parto, como citomegalovirus (CMV), rubéola, toxoplasma, enterovirus (EV), parvovirus B19 (B19V), virus del herpes simple (HSV) o hepatitis B (HBV), entre otros. La infección congénita por CMV (cCMV) es la más frecuente y la principal causa de sordera en los países desarrollados. Sin embargo, como sucede con la mayoría de las infecciones congénitas, permanece olvidada en entornos con recursos limitados, y se desconoce en gran parte su carga real y su impacto.

En muchos países de renta media o baja, al menos la mitad de las muertes de niños se producen en casa, a menudo sin haber sido visitados por un clínico. Sin embargo, en algunos casos, los niños mueren en casa justo después de haber sido atendidos en un centro sanitario. La mortalidad hospitalaria es un contribuyente bien conocido de la mortalidad infantil y se han desarrollado e implementado con éxito guías e intervenciones para reducirla. Aunque la mortalidad posterior al alta hospitalaria (PDM) puede ser tan alta como la mortalidad hospitalaria en entornos con recursos limitados, es un fenómeno olvidado y poco estudiado. De hecho no se han desarrollado guías, recomendaciones o estrategias adicionales para abordar los días inmediatamente posteriores a alta hospitalaria, el cual es un período crítico para la supervivencia infantil. La fragilidad de los sistemas de salud en LIC, los altos costos inasequibles para atender enfermedades agudas y la falta generalizada de conciencia sobre la carga y las implicaciones del PDM por parte de los trabajadores de salud y los responsables políticos explican en parte que la mortalidad durante el periodo inmediato al alta hospitalaria permanezca relegada al olvido.

Para alcanzar el nuevo objetivo de mortalidad infantil establecido por los Objetivos de Desarrollo Sostenible (SDGs) para 2030, es necesario mejorar el conocimiento en enfermedades graves en aquellos países con mayor morbi-mortalidad y desarrollar e implementar intervenciones para abordar las enfermedades que causan el mayor número de muertes entre los niños menores de 5 años.

Esta tesis pretende abordar cuestiones relacionadas con las enfermedades graves que causan la mayoría de las muertes en lactantes y niños menores de cinco años y para las cuales no se han implementado intervenciones específicas en Manhiça, un área semirural en el sur de Mozambique.