The developing immune system – from foetus to toddler

17/10/2023

Introduction

This article describes the events in the formation of the human immune system and the development of the innate as well as the adaptive arm of immunity. The steps during foetal, neonatal and early childhood are described in detail. The consequences for immunity to key infections are discussed. As knowledge in this field is expanding, the potential use of new diagnostics tools for early detection of invasive infections in the clinical management of paediatric patients is outlined as well.

The developing immune system – anatomy and histology

During foetal development, there is an ongoing modulation and shaping of lymphoid tissue. The haematopoietic system, along with the vascular and cardiac system, is one of the first to emerge during embryogenesis. Most knowledge here comes from murine models, complemented by observations from human embryos. The first blood cells, derived from mesoderm cells, are localized in the yolk sac at embryonicday (E) 6.5 in the mouse. These primitive cells then migrate and localize in the anterior region of the primitive streak in the embryo (E8.5) and develop to form erythroid progenitors (rev. by 1). It is believed that these early progenitors also give rise to granulocyte–macrophage progenitors as well as megakaryocyte progenitors. Thereafter, these haematopoietic stem cells (HSCs) are capable of seeding to the foetal liver and ultimately provide long-term haematopoiesis in the bone marrow (rev. by 2; BM; Fig. 1A). In human foetuses, the transfer of HSCs to the BM occurs around gestational age (GA; week) 20 and is mediated by the chemokine CXCL12 by the interaction with its receptor CXCR4 present on HSCs. The chemokine CXCL12, produced from BM stromal cells, has a crucial role in BM development. The rare human immune deficiency, the WHIM syndrome, caused by a mutation in the CXCR4 gene leading to gain of function, gives an insight into the importance of the CXCR4–CXCL12 interaction. These patients display neutropenia owing to retention of cells in the BM and hypogammaglobulinemia owing to defect organization of the germinal centres of the lymph nodes. Children with the WHIM syndrome also suffer from recurrent bacterial infections and increased susceptibility to human papilloma virus infections (3).

Key notes

• The development of the human immune system is a continuous process through embryogenesis as well as childhood.

• A failure to respond with an age-appropriate response will increase mortality and morbidity.

• Increased knowledge about the maturation of the immune system may lead to new diagnostic tools and therapeutic interventions.

The human thymus develops from the third pharyngeal pouch and cleft complex that gives rise to the thymic epithelium and thymic medulla. As early as GA 8, HSCs colonize the early thymus epithelial rudiments, and by GA 20, the organogenesis of the thymus is complete (4). By GA 16-20, T-cell development is well under way and T cells emigrate to form the peripheral T-cell pool. The development of T cells occurs in close contact with the thymic epithelial cells present in true epithelial spaces (TES). In children with DiGeorges syndrome (22q11.2 deletion), genes important for thymic organogenesis are affected and thus, thymic aplasia or hypoplasia occurs with profound T-cell deficiency as a severe consequence of this syndrome. This also points to the importance of interactions between supportive stromal cells and lymphoid progenitor cells for proper development of the immune system. Thymus also consists of a thymic perivascular space (PVS), which contains other lymphoid cells, granulocytes, mast cells and adipocytes. The human TES reaches its maximum size at 1 year of age, whereas the PVS peaks in size between 10 and 25 years of age. Thus, the total size of the human thymus is constant throughout life. Human thymopoiesis continues to occur in the TES also in adult life but with a reduced rate compared to the neonatal period (5).

Secondary lymphoid tissues such as spleen, lymph nodes and Peyer’s Patches are generated in utero and these are evident in human foetuses from GA 12 (6). In general, interactions between HSCs and stromal cells that occur during embryogenesis are essential for the formation of lymphoid tissue, but external stimuli are not required for normal development (rev. by 7). The interactions between these two cell subsets result in up-regulation of adhesion molecules and homoeostatic chemokines, which are required for further attraction and retention of HSCs in the lymph node. T cells appear in the early lymph node of the human foetus by GA 14 and by GA 17 also B cells can be found densely packed surrounded by follicular dendritic cells in the primary follicles. After birth, there is a steady influx of B and T cells as well of monocytes into lymphoid tissue as the child matures and is exposed to new antigens (rev. by 8). Other mucosa-associated lymphoid tissue localized in the nasal mucosa, tear duct and small intestine (cryptopatches) is formed after birth and requires immune stimulation, achieved by early bacterial colonization (rev. by 6).

The developing human immune system – innate immunity

The parts of the immune system that are responsible for the immediate defence mechanisms and ⁄ or that do not require previous exposure to a specific pathogen are traditionally referred to as innate immunity. Hallmark features are rapid pathogen clearance via the action of complement, antibodies and host cell lysis as well as phagocytosis-mediated killing of pathogens by granulocytes, monocytes ⁄ macrophages and dendritic cells. The recognition of pathogens relies on conserved biological patterns (pathogen-associated molecular patterns; PAMPs) exposed or shedded by the intruders. These motifs are recognized by host receptors (pattern recognition receptors; PRRs) such as toll-like receptors, NOD-like receptors, RIG-like receptors. Furthermore, cells of the innate system produce cytokines and present antigens that aid the initiation of the subsequent adaptive immune response.

With increasing GA, phagocytic cells are formed in the human foetus. First, monocytes appear in increasing numbers, and with concomitant improved expression of phagocytic Fc receptors, resulting in better phagocytic and antigen presenting capacity (9). When comparing adult and neonatal innate cells, neonatal cells are much less polyfunctional, and each individual cell produces fewer cytokines (10). Foetal ⁄ neonatal cells produce high levels of superoxide and display an increased production of chemotactic IL8. In contrast, a low production of classical pro-inflammatory cytokines is detected (10,11). The superoxide production, which in the end contributes to bacterial killing, represents a very primitive yet efficient response, which is evolutionary present already in nematodes (12). The difference between foetal and adult cells is more pronounced in whole blood, as compared to when purified cells are studied, implicating the role of soluble factors in neonatal blood (10). For example, the foetal inhibition of pro-inflammatory TNF production in response to bacterial lipopeptides is dependent on the high levels of adenosine in neonatal plasma (13). Adenosine, however, does not affect lipopeptide induced IL6 production, in all creating a response that is less pro-inflammatory (13). This ability to produce cytokines in response to infectious stimulus remains low for years. Monocytes from children have the capacity to produce TNF and IL6 to the same levels as adult monocytes around the age of 3 years (Fig. 1B), whilst a number of other cytokines such as IFNc and IL12 remain low until teenage (14).

Figure 1 A schematic figure of the development of the immune system before birth (A) and after birth (B).

In contrast to monocytes, neutrophils are scarce before GA 31, where after they increase exponentially to be the dominant white blood cell at term birth (15). The levels of circulating neutrophils the first week after birth may even exceed the levels in adults (16). The levels are normalized around 72 h post-partum. Apart from circulating cells, there is a reserve capacity in the form of neutrophil storage pools in the BM, liver and spleen. However, the functionality of the neonatal neutrophil is impaired, for example, they aggregate in response to chemotactic factors and they have reduced levels of surface adhesion molecules. This functionally translates into a reduced ability to adhere and extravasate from the bloodstream, as well as a reduced chemotactic ability (11, rev. by 17, rev. by 18). This phenomenon has been validated in a neonatal rat model, where upon infection, neutrophils are released from the storage pool but fail to home to the site of infection (19). This ability to migrate correctly reaches adult levels already when the full-term infant reaches birth weight, whilst in pre-term infants, this is delayed with months (20; Fig. 1B). The biological significance of neutrophil motility for resistance to infection is shown by the fact that children that are delayed in the maturation of neutrophil migration are more susceptible to infections (21). In addition, neonatal neutrophils are further impaired, in that they are less able to generate bactericidal substances such as lactoferrin (rev. by 17).

The functionality of the third type of phagocytic cell, the foetal conventional ⁄ myeloid dendritic cell (cDC) is very similar to the foetal monocyte (10). These cells produce less IL12, which is a central cytokine to cDC. IL12 can be viewed as a link from innate immunity, to the activation of adaptive immunity, which hence is impaired early in life. The other type of dendritic cell, the foetal ⁄ neonatal plasmacytoid dendritic cell (pDC) is even further impaired, and produces very little IFNa, whether or not purified or in whole blood (22). The levels of both types of DC increase with age, with a doubling at about the age of 5 years. Children with a delayed DC maturation have a higher frequency of lower respiratory tract infections (23).

The innate system also includes natural killer (NK) cells. These cells have that capacity to detect and destroy virusinfected cells through a cytotoxic mechanism. The NK cell function is controlled by a balance between activating and inhibitory receptors (24). The absolute numbers of NK cells correspond to the GA of the human foetus, and reaches maximum levels at birth. The levels then drop progressively, to reach adult levels around the age of 5 years (25; rev. by 26). Although the numbers of NK cells in young children are high, the functionality of these cells is very different, in that the cytotoxicity is much lower. This probably results from very poor levels of activating cytokines, because cytotoxicity can be restored in vitro by added cytokines (rev. by 26, rev. by 27). The monocyte development and cytokine production are thus crucial for the progress of NK cell function.

Apart from cells, complement factors, which are produced in the liver, contribute to the innate, immediate defence. These factors are involved in amongst other things immune cell recruitment to site of infection, neutralization and supportive functions for efficient phagocytosis, where the latter is probably the most important function. Complement components in neonates are reduced to 10–70% of adult levels (rev. by 18). However, the levels of complement components normalize rapidly (Fig. 1B).

Thus, the innate system develops during the first years of life. Very ancient responses, such as the production of superoxide, are apparent early in development. Pre-natal responses are in favour of immune-suppressing cytokines. Most of the innate immune maturation takes place before school age, but full capacity is not reached until teenage.

The developing human immune system – adaptive immunity

In contrast to the innate system, the adaptive arm is aimed at eliminating specific pathogens, and at immunological memory. This is achieved through the action of several types of T cells and B cells. Through embryogenesis, lymphocytes increase in a linear fashion with GA (15). During the first weeks after birth, the neonate experiences a massive increase in lymphocytes. This expansion is largely independent of GA at birth, even though lower levels in total are detected at lower GA (25). Lymphocyte development is, hence, thought to be linked to extra-uterine life.

The levels of T cells are high at birth and increase even further the first year, to then decrease and normalize to adult levels in school children (25,28). However, functionality is poor. The low foetal production of IL2, as IL2 is central to T-cell function (29), is one likely reason for the low quality of T-cell responses in the small child. Furthermore, clinical observations from the very mild symptoms of a toxic shock syndrome in neonates indicate a general T-cell anergy also in response to superantigen (30).

T cells are grossly divided into cytotoxic CD8+ T lymphocytes, which function in killing infected cells, and CD4+ T helper cells, which mainly aid the function of other cells by providing cytokine stimulus. Neonatal cytotoxic T cells are less prone to respond and require more stimulus to do so (31). T helper cells can be further subdivided into effector cells and regulatory cells. The effector cells can be of different subclasses (Th1, Th2, Th9 and Th17), and what type of effector cell that dominates will have major implications for  the capacity to eliminate a pathogen. In the foetus, there is a strong Th2 polarization, exemplified by the impaired IFNc production by T cells (29). This results in a reduced or modified immune response to certain infections. The regulatory cells, in contrast, function to suppress immune responses. These cells are present in very high numbers in human cord blood and are highly suppressive in their function (32).

Both CD8+ and CD4+ T cells can develop into memory cells. These cells are formed after an infection and have the potential to respond immediately if the child is exposed to the same pathogen again. Such cells develop over lifetime, and in healthy neonates, very low levels are detected, and the levels remain low even in older children (25).

In summary, the foetal and neonatal T-cell response is shifted towards the suppression of cytotoxicity and suffers from inexperience. During the first year, cell functionality is gained, but the lack of experience remains through childhood.

B cells are abundant at birth (25) and follow a similar kinetic as T cells, where there is an initial increase, and then over the first years a gradual decrease to adult levels (28). Phenotypic analyses by flow cytometry clearly show that the majority of these cells are naı¨ve, immature B cells (approximately 95% of total B cells; 25). The proportion of these different B-cell populations slowly changes towards an adult peripheral B-cell compartment. In 5- to 10-year-old children immature B cells have dropped to a level of 20% but are still not at the adult 10% level (25). During foetal life, there is a lack of antigenic stimulation, which is reflected by the low number of memory B cells present at birth (25). The frequency of switched (IgG+) and non-switched (IgG)) memory B cells increases slowly with age and reaches adult levels in children 10–15 years of age (33; Fig. 1B).

The effector of the humoral arm of the adaptive immune system is the immunoglobulin (Ig) molecule, which in humans exists in the isotype forms of IgM, IgA, IgG (and IgE; not further discussed). These Igs exert their function by directly neutralizing pathogens by attaching to the surface and thus, inhibiting interactions with human cells and further infection. By binding to foreign particles, Igs also facilitate opsonization by phagocytic cells that express Fc receptors with the ability to bind to antibody–antigen complexes. IgA also protects mucosal surfaces by ‘coating,’ thus preventing damage of the epithelial barriers and pathogen invasion (34).

After antigen encounter, IgM is the first antibody to be secreted followed by IgG and ⁄ or IgA, which are formed after class switch in the Ig locus (35). In the newborn, IgM is the most commonly found immunoglobulin because class switch is a rare event during normal intrauterine development and only a few IgG+ and IgA+ B cells can be found in term cord blood. After birth, exposure to foreign antigens increases dramatically, which increases the proportion of class-switched cells in both pre-term and term infants. However, the diversity of the IgG repertoire in pre-term infants increases slower than in term infants and remains low until an age corresponding to end of the gestation (36). At 1 year of age, the IgG levels in children have reached approximately 70% of adult levels but only 30% of adult IgA levels. It is important to consider class switch in relation to the antigen structure as well, because it is long known that the young child has impaired antibody (Ab) responses to polysaccharide antigens, best exemplified by the encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis). The Ab response to polysaccharides is a T-cell-independent response and occurs mainly in the marginal zone of the spleen. Histological studies of the infant spleen show that this zone is not fully developed until 2 years of age, which may in part explain the delayed Ab response towards encapsulated bacteria (37). Reduced levels of the complement receptor CD21 on B cells and low complement activity in infants have also been implicated in the reduced Ab response towards polysaccharides.

Despite the initial low production of IgG, the infant has a functional antibody response from the maternal side (Fig. 2). Transplacental transport of IgG occurs via a neonatal Fc receptor (FcRn) that is present on adverse syncytiotrophoblasts in the placenta, and during the third trimester, increasing amounts of maternal IgG are being transferred over placenta so that foetal IgG titres exceed maternal IgG titres at birth. Maternal IgG represents the mother’s immunological memory and can protect the offspring during the first 6 months of life. If the mother is well vaccinated, the child is protected against tetanus and maternal antibodies may also protect against diphtheria, pertussis and other infections. Pre-term infants will have less maternal IgG and antibodies directed against these pathogens wane earlier in pre-term infants (38). This suggests that more studies are needed on immunization schedules for pre-term infants to reduce morbidity and mortality in diseases such as pertussism (Textbox 1).

Figure 2 Maternal transfer of antibodies to the infant occurs via placenta and breast-milk and affects several arms of the immune system in the offspring

Future Areas of Research

In children with signs of ascending infection due to chorioamnionitis not all succumb to early onset sepsis. What can we learn from the immune response in the children who stay healthy and can these observations lead to new therapeutic interventions?

The development of new diagnostic tools for invasive infections in the newborn is of great importance. How do we evaluate these tools in the best possible way with large cohorts of patients included?

Infections early in life, are very common and antibiotic treatment is used generously. How does extensive antibiotic therapy affect growth and development later in life?

Maternal antibodies are important for disease protection early in life. Could maternal immunization during pregnancy be a way to increase antibody protection in term babies?

During a limited neonatal period, maternal antibodies also shape the B-cell repertoire of the infant by imprinting (rev by 39). This process has been shown to exert immunomodulatory life-long effects in the offspring. In mice, it has been shown that maternal non-antigen reactive antibodies (anti-idiotypic antibodies) enhance microbial protection and converse primary immune responses into secondary antibody responses after immunization. Maternal antibodies may also transfer autoimmune disease, exemplified SLE by proxy. Maternally derived auto-antibodies directed against RNA-binding proteins Ro and La are strongly associated with congenital heart block that may develop long after the disappearance of maternal antibodies (rev. by 40).

Neonatal mucosal immunity can be modified by breastfeeding, where secretory (s) IgA and IgG are being transferred together with cytokines, antibacterial peptides and other immune cells to the infant. Secretory IgA in breast milk is highly reactive against pathogens occurring in the environment of the mother and child because sIgA reflects antigenic stimulation in gut and airway lymphoid, but also sIgA directed against food antigens can be found. Interestingly, the immune cells present in milk produce cytokines, which participate in the development of IgA-producing cells in the infant (41). Thus, breast-milk has immunomodulatory properties that result in sub-clinical, rather than clinical infections, which gradually stimulate IgA memory towards potential pathogens whilst it also suppresses inflammation.

Consequences of the developing human immune system for foetal development – transitions at birth

The delicate process of foetal development should evidently not be disturbed by inflammatory reactions. To avoid inflammation, foetal cells such as macrophages are hyporesponsive, and soluble inflammatory mediators are scarce (13, rev. by 42). Similarly, neonates that experience a severe bacterial infection respond with reduced cytotoxic capacity of the NK cells, whereas toddlers respond by NK cell activation (rev. by 26). If intrauterine production of pro-inflammatory cytokines despite all occurs, it associates with intrauterine growth restriction and spontaneous abortion (rev. by 18). The preferred physiologic response to foetal ⁄ placental inflammation though appears to be induction of labour, as production of pro-inflammatory cytokines- ⁄ Th1-polarizing cytokines associates with premature labour (rev. by 18). Also, foetal IL8 production associates with premature rupture of the membranes, and labour (43). This combination of inflammation and pre-term birth predisposes to organ damage. For example, chorioamnionitis before GA 28 leads to increased risk of bronchopulmonary disease, where the severity of inflammation can be correlated to the degree of disease (44). It does, however, matter how the foetus responds: if IL6 production predominates, this lead to hastened lung maturation with improved outcome (rev. by 18). On the other hand, if the neonate responds by TNF production, this leads to lung disease (rev. by 18). So, in the foetus, a pro-inflammatory response is destructive for lung development. For other tissues, other principles apply. Increased foetal serum levels of IL6 as well as intracerebral levels of TNF both correlate to adverse neurologic outcome (44).

The transition of the full-term neonate from the uterus to the outside world is in fact a transition from a sterile site, to a colonized one. The foetus must adapt to this, without being overwhelmed by inflammatory stimuli that might be hazardous. As mentioned earlier, a Th2 response characterizes the foetal response. The cells produce less IFNa, IFNc, IL12 and more IL1b, IL6, IL23 and much more IL10 (10). Upon birth, this must be altered towards a Th1-type response (Fig. 1B), and infants that are delayed in this shift have an increased frequency of blood steam infections early in life (45). It has also been noted that children who have experienced Epstein Barr virus and Cytomegalovirus infections retain the Th2 profile at least to the age of 2 years, and that this may increase the likelihood of allergies later in life (46). These data are in agreement with the so-called hygiene hypothesis, where innate stimulation early in life leads to a Th1-tilted response and decreased incidence of allergy and asthma. However, recent data suggest that exposure timing, antigen dose and the genetic background of the child are crucial to whether antigen exposure will lead to beneficial or deleterious effects (47).

The development of mucosal immunity in the newborn is closely linked to the colonization of the gut by commensal bacteria where initially, infants are colonized with Escherichia coli and Streptococcus species. During early colonization, microbial products (LPS from Gram-negative bacteria) in the gut lumen bind to toll-like receptors (i.e. TLR4) on epithelial cells and thereby dampen signalling via these receptors that otherwise would create a harmful inflammatory response in the gut. This is one important mechanism for the induction of oral tolerance in newborns, which explains why most infants show no adverse immune reaction when exposed to environmental and dietary proteins (48). In this context, it is interesting that failure to downregulate TLR4 signalling in pre-term infants has been associated with the development of necrotizing enterocolitis (NEC; 49).

Thus, for the growing foetus, immune stimulation appears harmful for normal development. Furthermore, upon birth, it appears that the neonate must balance immunity maturation so that a shift to extrauterine responses is sufficient but not adult like. A failure to shift to post-natal immune regulation results in increased susceptibility to disease, or adverse reactions.

Consequences for infection susceptibility after birth

For the pre-term child, the combination of a poorly developed immune system and long-term hospital care is not optimal. Infection is shown to be an independent predictor of poor outcome in pre-term children, irrespective of other circumstances (50). The innate defences are compromised at several levels. First, the reduced neutrophil storage pools, as well as the low ability to produce new progenitors, lead to neutropenia (rev. by 17, 51). Neonatal neutropenia affects 1 ⁄ 5 of all children with a birth weight below 1500 g (16). This is of great importance to Gram-negative infections, where neutrophil pools are exhausted rapidly (52). The clinical importance of this observation is verified by the observation that treatment of such children with granulocyte colony–stimulating factor reverses the neutropenia – with a subsequent drop in sepsis incidence (rev. by 27). Second, the limited numbers of neutrophils that do circulate in pre-term neonates have a much lower level of complement receptor 3 (CR3) than neutrophils from fullterm neonates (53). This means that the capacity of the neutrophil to adhere is impaired. The levels of CR3 in foetuses approach those in patients with a non-complete leucocyte adhesion deficiency, a condition that predisposes to recurrent infections (54). This is further exacerbated by the generally reduced phagocytic capacity in the pre-term infant, which most likely is the reason for the increased susceptibility to encapsulated bacteria, such as group B Streptococcal infections. Complement and antibodies alone do not kill such bacteria, but also require functional phagocytes (rev. by 27). This reduced bacterial clearance capacity, leads to a more continuous bacteraemia (19). Third, the lower level of maternal antibodies in pre-term infants leads to further impairment of innate defences. The combination of low levels of complement and antibodies leads to poor phagocytosis by neutrophils in the pre-term child (rev. by 17).

The limitations and the inexperience of the developing immune defence render also older children of different ages more susceptible to infections. The described low levels of memory cells and the general immaturity of the immune system make children more susceptible to both viral, and bacterial, infections in general. Similarly, the lack of interferon-mediated inhibition of viral replication makes it more difficult for children to control a viral infection. Despite this, the generation of specific cytotoxic T cells is crucial for viral clearance and recovery. For example, the cytotoxic T cell response against Herpes Simplex Virus (HSV) in neonatal mice differs from that seen in the adults; the primary response is delayed and displays a lower capacity for specific lysis of infected cells as well as impaired expansion of antigen-specific cytotoxic T cells. Thus, after mucocutaneous infection by HSV, there is a relative difficulty in controlling the infection that may contribute to disseminated disease in infants (55).

Future diagnostic tools

There is an expanding array of experimental diagnostic markers available for neonatal invasive infection, of which basically only procalcitonin (PCT) is in clinical use. PCT is indeed increased during severe infection in neonates (56). The problematic part of using PCT as a marker is the rate of false positives. There is a natural PCT rise between 18 and 30 h of life, irrespective of GA (57). PCT is also increased in children that have been hypoxic, has a respiratory ⁄ hemodynamic failure or with respiratory distress syndrome (56,58). In addition, PCT is increased (to the same levels as sepsis) after chorioamnionitis, even if the child is healthy (57). Despite these cases of false positives, PCT remains, in many cases superior to C-reactive protein (CRP) in predicting sepsis (59).

Other methods that are in experimental use include assessments of infection-associated cell-surface molecules, infection-associated cell anergy, measurements of cytokines, tissue markers and coagulation factors. The first two of these can be used as screening tools, and the others are used for the verification of diagnosis upon suspicion of infection. Example of the first, is the measurement of CD11b density on phagocytes, which is significantly increased in pre-term neonates already 3 days before symptoms of invasive disease (60). Similarly, lack of cell functionality as a response to infection can be detected as reduced phagocytosis of bacteria by monocytes in whole cord blood prior to early on set sepsis in pre-term neonates (61). The more verifying soluble markers include SICAM, CRP, CD62E and serum amyloid A in combination, or Lipopolysacharide-binding protein or IP-10 as single markers (62–64). For more severe invasive disease, with disseminated intravascular complications, markers such as increased IL10, IL6 and decreased RANTES have a sensitivity of 100% for the detection of invasive disease d(65).

For children, as already described for pre-term neonates, there are many markers that have proven good, but that are not in clinical use yet. Again, PCT is the only new marker that is readily available. PCT has proven better than CRP for diagnosing sepsis (and severity thereof) when measured at admission in children over 28 days (66). PCT is also better at identifying children with meningococcal disease amongst children with fever and rash (67). Similarly, LBP is high in children with sepsis and can be of diagnostic value (68). In addition, neutrophil CD64 indices are good markers for sepsis in children (64).

Thus, there are a number of potential markers that are now being tested experimentally, which may aid the development of new tools for the identification of severely infected children.

Comments & challenges ahead

This review summarizes recent knowledge on the development of the immune system and how this may affect susceptibility to infection, as well as finding new diagnostic tools is important areas of research. The increasing levels of antibiotic resistance as well as the lack of knowledge of the effects of extensive antibiotic treatment early in life are important points here. Also, the understanding of the young child’s natural response to infections may inspire the development of new treatment regimens (Textbox 1).

Acknowledgements

This work has been supported by funding from Sa¨llskapet Barnava˚ rd, Stiftelsen Lars Hiertas Minne, Stiftelsen Frimurarna Barnahuset, Socialstyrelsen, Magnus Bergwalls Stiftelse & HKH Kronprinsessan Lovisas fo¨ rening fo¨ r barnsjukva˚ rd ⁄ Stiftelsen Axel Tielmans minnesfond. Thank you to Benedict Chambers for comments and discussions.

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