Recognition of the primary infection by Pneumocystis in infants: A silent threat to public health

Publishable summary: 

Increasing evidence suggests that the most common respiratory infection affecting infants is the mild and stealth, primary infection by the micro-fungal organism Pneumocystis. This infection goes currently unrecognized and has been neglected as a subclinical irrelevant infection by contrast with the severe Pneumocystis pneumonia affecting the immunocompromised host. However, compelling new evidence suggests that this infection may be pathogenic to certain infant age groups and that microbiome-host interactions in early life may condition the development of altered immune responses in older infants or adults. They underscore the importance of understanding this highly prevalent subclinical Pneumocystis primary infection. This infection is acquired close to birth, develops over a period of few weeks, and peaks between the ages of 2 to 5 months. Furthermore, this age interval period coincides with the peak of infant respiratory morbidity and post-neonatal mortality, raising the hypothesis that a pathogenic role of Pneumocystis in infants is possible provided the near-universal prevalence of this infection at that particular age window. This hypothesis is strengthened by the recent demonstration of pathology consisting of increased mucus associated to Pneumocystis in infant lungs in line with observations in animal models from us and other research groups that show Pneumocystis-associated transient respiratory impairment and airway remodeling. Importantly, Pneumocystis has been detected in lung of aborted fetuses, which may suggest vertical transmission and an eventual co-factor role in abortion and in newborn respiratory distress due to the demonstrated ability of Pneumocystis to decrease pulmonary surfactant. Therefore this proposal aims to recognize the epidemiology of this silent infection in preterm and term otherwise healthy newborns and small infants in different countries, to recommend a preferred method for diagnosis by comparing sensitivity of available methods of known specificity, to characterize the pulmonary myco-microbiome using metagenomic analyses, and additionally, to understand the Pneumocystis-airway epithelium interaction using transcriptomic studies to identify the host-activated gene responses associated to this unique fungal pathogen in infant lung specimens. The proposal will importantly explore Pneumocystis-associated breathprints using non-invasive detection of volatile organic compounds (VOC) in exhaled air that may prove as an ideal method to recognize stealth infections especially in prematures and small infants. Recognition of the wide distribution of Pneumocystis epidemiology will be in itself a measure of success of this proposal and, furthermore, understanding this early life infantmicrobial interaction may lead to prevent infant and, additionally, older age respiratory morbidity. Therefore, results of this proposal will contribute to prevent infectious-related morbidity and promote well being, by increasing our recognition and understanding of this early-life and highly frequent Pneumocystis primary infection.