key: cord-0787687-fi54ip80 authors: Van de Perre, Philippe; Molès, Jean‐Pierre; Nagot, Nicolas; Tuaillon, Edouard; Ceccaldi, Pierre‐Emmanuel; Goga, Ameena; Prendergast, Andrew J.; Rollins, Nigel title: Revisiting Koch's postulate to determine the plausibility of viral transmission by human milk date: 2021-03-08 journal: Pediatr Allergy Immunol DOI: 10.1111/pai.13473 sha: a2d16e2b0d0fd0069ff4a28baedf9448c733f8e4 doc_id: 787687 cord_uid: fi54ip80 As breastfeeding is of utmost importance for child development and survival, identifying whether breast milk is a route of transmission for human viruses is critical. Based on the principle of Koch's postulate, we propose an analytical framework to determine the plausibility of viral transmission by breast milk. This framework is based on five criteria: viral infection in children receiving breast milk from infected mothers; the presence of virus, viral antigen, or viral genome in the breast milk of infected mothers; the evidence for the virus in breast milk being infectious; the attempts to rule out other transmission modalities; and the reproduction of viral transmission by oral inoculation in an animal model. We searched for evidence in published reports to determine whether the 5 criteria are fulfilled for 16 human viruses that are suspected to be transmissible by breast milk. We considered breast milk transmission is proven if all 5 criteria are fulfilled, as probable if 4 of the 5 criteria are met, as possible if 3 of the 5 criteria are fulfilled, and as unlikely if less than 3 criteria are met. Only five viruses have proven transmission through breast milk: human T‐cell lymphotropic virus 1, human immunodeficiency virus, human cytomegalovirus, dengue virus, and Zika virus. The other 11 viruses fulfilled some but not all criteria and were categorized accordingly. Our framework analysis is useful for guiding public health recommendations and for identifying knowledge gaps amenable to original experiments. Exclusive breastfeeding in the first six months of life and continued breastfeeding for at least 24 months are the optimal feeding mode for infants and children. Breastfeeding not only provides optimal nutrition but also contributes significantly to child survival, lifelong health, and development. 1 Breast milk contains a multitude of biologically active substances (including antibodies, cytokines, anti-infectious agents, cell growth factors, complex lipids, immunomodulating oligosaccharides, and complement) and maternal cells that confer benefits to enable these outcomes. 2 It is now understood that the fragile neonatal immune system only becomes fully competent if it is complemented by components of the maternal immune system transferred through breastfeeding during the first few weeks postpartum so-called "fourth trimester of pregnancy." The interactions and intimacy between mother and infant through breastfeeding also support neuropsychological maturation and early childhood development. However, in some very specific conditions, breast milk and breastfeeding can be important routes for viral transmission. For at least three human viruses-the human T-cell lymphotropic virus 1 (HTLV-I), the human immunodeficiency virus (HIV), and the human cytomegalovirus (CMV)-breastfeeding contributes to motherto-child transmission. Several other human viruses have also been hypothesized to be transmitted through breast milk or by breastfeeding because of observations such as the presence of viral particles or viral genomes in breast milk or the acquisition of the infection by infants fed by mothers with confirmed infection. For many of these viruses, the experimental or observational data linked to actual transmission remain piecemeal and incomplete, rendering the causality of the relationship still elusive. Definitive proof of a causal link between the infant feeding modality and infectious risk is particularly difficult to ascertain and is presently not based on a consensus framework for the interpretation of evidence. The portal of entry for milk-borne viruses in the breastfed infant remains to be fully clarified but may involve tonsils, pharyngeal mucosae, and digestive tract mucosae, including enterocytes and Peyer's patches. 3, 4 Various mechanisms are used by human viruses to cross infant's mucosae and establish infection, including direct translocation facilitated by breaches in the mucosal integrity, cell-to-cell transfer via virological synapses, transcytosis across M cells or enterocytes, or possibly by breastfeeding-induced microchimerism. [3] [4] [5] [6] [7] Differentiating transmission through breast milk-as a result of ingesting milk containing the virus-from breastfeeding transmission, which might also include other transmission routes (airborne, droplets, skin or mucous contacts, blood-borne, vector-borne) due to proximity with the mother during feeding-is challenging. A recent example of such difficult and inconsistent interpretation of evidence was generated during the coronavirus disease 19 (COVID- 19) pandemic. Studies reported that severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) can be transmitted by approximately 10% of infected pregnant women to their offspring, in utero or in the first weeks of life. 8 Also, SARS-CoV-2 RNA has been detected in the breast milk of lactating mothers with confirmed SARS-CoV-2 infection and mild COVID-19 symptoms. 9 Whether breast milk and/or breastfeeding transmission of SARS-CoV-2 is possible and, if so, whether this transmission represents a significant threat to infant health remain to be demonstrated. This uncertainty has generated scientific questioning and also anxiety in the public and a significant threat to infant feeding practices worldwide. The World Health Organization has reviewed this evidence and released recommendations, but other national authorities and professional associations have not always concurred with these guidelines. 10 Here, we propose an analytical framework based on 5 criteria to help establish a causal relationship between breast milk exposure and acquisition of viral infections in breastfed infants. Based on revisiting the concept of Koch's postulate, this analytical framework should help refine health policies regarding infant feeding and infectious risk and stimulate research to fill the gaps in order to confirm or refute breast milk transmission of specific human viruses. The first Koch's postulate was proposed in 1876 by Robert Hermann Koch in a pioneering attempt to establish the causative relationship between a microbe and a disease. In its initial form (followed by many revisions), the postulate included the following four criteria: -The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms. -The microorganism must be isolated from a diseased organism and grown in pure culture. -The cultured microorganism should cause disease when introduced into a healthy organism. -The microorganism must be re-isolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent. 11 The postulate implies that the demonstration of the presence of an infectious agent in a patient affected by the disease is not sufficient to infer a causal relationship. In that sense, Koch's postulate is considered as a founding concept of modern evidencebased medicine. Koch's postulate focused particularly on acute disease causation, as chronic viral infections were clearly not a concern at that time. One hundred and forty-four years later, the Most frequently, this can be assessed in carefully described case reports, case series, or cohorts. Other routes of mother-to-child transmission can be potentially ruled out by demonstrating the absence of virus detection in cord blood and/or the birth canal or by demonstrating a risk reduction by avoidance of breastfeeding (strict replacement feeding) or by viral inactivation of expressed breast milk (pasteurization, freezing-thawing, etc). Oral inoculation by means of culture supernatant or concentrated infected cells is less convincing, as it is not reproducing the complex composition of breast milk and its interactions with viable viruses. In order to challenge this analytical framework, we searched for evidence in published reports to determine whether the 5 criteria are fulfilled or not for 16 human viruses that are suspected to be transmissible by breast milk. 6, 8, 9, According to the literature search, information can be found to validate or not the criteria for these viruses, although this information is sometimes scarce or incomplete. As an example, animal model exists for almost all 16 viruses, but few of these models have been challenged by the oral route and a fortiori by breast milk. 13 We considered breast milk transmission is proven if all 5 criteria are fulfilled, as probable if 4 of the 5 criteria are met, as possible if 3 of the 5 criteria are fulfilled, and as unlikely if fewer than 3 criteria are met. If at least two criteria were not reported, viral transmission by breast milk was considered as insufficiently documented. According to this analytical framework (see Table) , transmissibility Human Over recent years, outbreaks of emerging or re-emerging viral infections have raised the question of transmission through breast milk and breastfeeding. As unknowns create anxiety and may impact feeding practices inappropriately, we believe our analytical framework contributes an important step in the process by which None of the authors have conflict of interest to disclose. The peer review history for this article is available at https://publo ns.com/publo n/10.1111/pai.13473. 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