Abstract

The pattern of infections in the first years of life modulates our immune system, and a low incidence of infections has been linked to an increased risk of common childhood acute lymphoblastic leukemia (ALL). We here present a new interpretation of these observations - the adrenal hypothesis - that proposes that the risk of childhood ALL is reduced when early childhood infections induce qualitative and quantitative changes in the hypothalamus–pituitary–adrenal axis that increase plasma cortisol levels. This may directly eliminate leukemic cells as well as preleukemic cells for the ALL subsets that dominate in the first 5–7 years of life and may furthermore suppress the Th1-dominated proinflammatory response to infections, and thus lower the proliferative stress on pre-existing preleukemic cells.
Keywords:

acute lymphoblastic leukemia, etiology, infections, immune system, cortisol, adrenal




Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in Europe and the United States with an annual incidence of 3.0–3.5 per 100 000 children 0–14.9 years of age.1 Only a small proportion of cases can be attributed to genetic predisposition such as Down syndrome or ataxia telangiectasia, and siblings of children with ALL do not seem to have a significantly increased risk of ALL.2 In contrast, considerable temporal and geographical variation in childhood ALL incidence is believed to reflect a correlation with the level of socioeconomic development suggesting a significant role for environmental factors in the pathogenesis of ALL.3, 4

There is strong epidemiological evidence that infections in the first years of life influence the risk of common childhood ALL. Different scenarios have been offered to explain this association, but the biological mechanisms underlying it remain to be established.5 Here we propose a novel hypothesis—the adrenal hypothesis—that proposes that the risk of childhood ALL is reduced with increasing infectious disease pressure in early life, as such infections raise plasma cortisol levels and thus eliminate leukemic cells as well as the preleukemic cells for the ALL subsets that dominate in the 2–5 years age incidence peak group. The adrenal hypothesis emerges from the following observations:

1. The ALL incidence shows a peak before 5 years of age, which is far more prominent in developed countries than in less affluent countries.
2. In Western industrialized countries, 80% of B-lineage ALL cases, which constitute the age-related incidence peak, harbor either an ETV6/RUNX1 translocation or a high-hyperdiploid leukemic clone. Both these subsets are frequently initiated prenatally and have an extended preleukemic phase.
3. One percentage of healthy newborns harbor translocation t(12;21)[ETV6/RUNX1]-positive cord blood cells, that is 100-fold their risk of developing ETV6/RUNX1-positive ALL. Thus, the kinetics of disappearance of such 'preleukemic' cells in the first 1–2 years of life could influence the subsequent risk of ALL.
4. Glucocorticosteroids (GCs) are among the most effective antileukemic agents. The ALL cases that occur in early childhood are especially sensitive to GC.
5. Adrenocorticotropic hormone (ACTH) therapy can induce cortisol levels, which leads to morphological remission in ALL.
6. During infection-induced stress, the ACTH response may increase cortisol secretion to levels that are equipotent to the GC levels obtained with GC-based antileukemic therapy.
7. Severe infections may induce morphological remission in childhood ALL.
8. Daycare attendance significantly increases the risk of infections and is associated with reduced risk of childhood ALL.
9. In developing countries, both the high burden of severe infections and malnutrition may contribute to a reduced occurrence of childhood ALL, as it increases both the cortisol secretion during infections and the cellular response to cortisol.

Childhood ALL, of which 90% are of B-lineage, is roughly composed of the following subgroups:

1. ALL in infancy, which frequently involves translocations of the MLL gene on chromosome region 11q2.3 and has a poor prognosis.6
2. An ALL incidence peak group that occurs between 2 and 7 years of age, of which 80% in developed countries harbor either of two mutations: a chromosomal translocation t(12;21)(p13;q22)[RUNX1/ETV6] or a high-hyperdiploid karyotype (greater than or equal to51 chromosomes).7 Both these subsets have a high cure rate with low to moderately intensive GC-/vincristine-/antimetabolite-based chemotherapy. Epidemiologically, this incidence peak is either absent or far less pronounced in the developing world.
3. A biologically heterogeneous group that includes T-cell ALL, cases with translocations t(9;22) and t(1;19), AML1 amplification, dic(9;20), hypodiploid ALL and numerous other recurrent leukemic mutations. This group lacks a prominent age incidence peak, and the relapse rate is generally high with GC-/vincristine-/antimetabolite-based chemotherapy.1, 7

No study clearly supports that underreporting and misdiagnosis explain the lower registered incidence of childhood ALL in developing countries, compared to that in Europe and the United States.3 In contrast, the available register-based data on ALL incidences by country and age group support that the incidence of ALL among children below 5 years of age is truly reduced with lower standards of living. Thus, the incidence of ALL is inversely related to the all-cause child mortality before the age of 5 years, which is a reliable marker for the standards of living (Table 1).4, 8 This inverse relationship is strongest for the leukemias in the 0–4 year age group, more moderate for ALL incidence in children 5–9 years and least so for the incidence of ALL in children above 10 years of age (Figure 1). As a result, the ratio of the ALL incidence in the 0–4 year versus the 10–14 year age group is strongly correlated to the all-cause child mortality before the age of 5 years (rS=-0.63, P<0.001) (Figure 2). Thus, the combined proportions of high-hyperdiploid and ETV6/RUNX1 translocation-positive cases appear to be lower in developing countries than in Europe and the United States. Consequently, the relative frequency of other subsets such as T-lineage ALL is higher in developing than in developed countries.9 Accordingly, a country like Ecuador may have an overall ALL incidence rate that is as high as that in the Nordic countries (around 40 per 1 000 000 children per year), but the ratio of ALL among the 0–4 year versus the 10–14 year age group is twofold higher in the Nordic countries than in Ecuador (Table 1).

The natural history of ETV6/RUNX1-translocated ALL has been studied extensively. The majority of such cases, as well as high-hyperdiploid ALL, seem to arise as a consequence of a two (or more)-hit process,10 where at least the first hit occurs in utero.11 Thus, chimeric genes or clonal immune gene rearrangements have been demonstrated in Guthrie cards from children who later developed ALL.11, 12, 13, 14, 15, 16 It is worth noting that ETV6/RUNX1 translocations have also been demonstrated by reverse transcription-PCR in approximately 1% of healthy newborns at a level of 10-3–10-4 cells17 and in 1% of healthy blood donors, although at a two-log lower frequency.18 Accordingly, the risk of common ALL in the 2–5 year age group is likely to reflect both the persistence and level of preleukemic cells in the child and the risk of these being affected by further leukemogenic mutations. Less is known of the preleukemic (subclinical) phase for other subsets of childhood ALL, but Guthrie card and twin/triplet studies indicate that t(1;19)(q23;p13)[E2A-PBX1] translocation-positive cases and T-lineage ALL in general are initiated postnatally.19, 20, 21

GCs are among the most important and effective inducers of apoptosis in normal and malignant lymphoblasts both in vitro and in vivo.22, 23 As monotherapy, both prednisolone and prednisone, which after absorption rapidly is converted to prednisolone, can induce morphological remission. In combination with vincristine, remission is obtained in 85% or more of all children with ALL. The profound GC sensitivity of common childhood ALL is illustrated by the four-log reduction in the leukemia burden in the bone marrow during a 4-week GC-containing induction therapy (=daily leukemic reduction of approximately 30% (0.728)).24

In the early 1950s, ACTH was shown to be effective in childhood ALL, which probably reflects that high plasma cortisol levels can induce morphological remission in a large proportion of childhood ALL.25

During infections, otherwise healthy as well as malnourished individuals may experience high ACTH-induced plasma cortisol levels.26, 27, 28, 29, 30, 31 During severe infection, these levels may be equivalent to prednisolone concentrations following a single dose of 20 mg/m2 in children with ALL. Here, the median peak level is 221 ng/ml, which corresponds to 613 nM prednisolone or 2453 nM cortisol, given an equipotency of 1:4.32 Furthermore, during infections, high cortisol concentrations can be maintained for several days in contrast to the transient concentration peaks following antileukemic prednisolone treatment.33

Not only may the cortisol secretion during infections rise to antileukemic treatment levels, but before the widespread availability of effective antileukemic therapy during the last decades, there were many reports of children with lymphoblastic leukemia who went into complete morphological remission following severe infections.34, 35, 36

By analogy, we speculate that infections and high cortisol levels accompanying infections could also eliminate preleukemic cells. In accordance with this, many, although not all, studies have shown a protective effect of preschool daycare attendance, which can be regarded as a surrogate marker for the burden of childhood infections.5, 37 Several previous reports have been hampered by their patient selection or risk of recall biases, but two recent and large childcare studies less prone to these sources of error have both shown a reduction in the risk of childhood ALL in the range of 40%.38, 39 So far unexplained, a recent British study has indicated that very early infections during infancy may occasionally increase the risk of ALL.40 During this early period of life, the circadian hypothalamus–pituitary–adrenal axis is still immature, and the data indicate that the impact of infections on the risk of ALL could depend on the time frame of the development of the immune system.41, 42

As the standards of living improve, some of the most significant health changes in early childhood are the access to clean water, the reduction in household size and sufficient nutrition. These factors can influence the risk of infections, the basic level and intermittent rises in endogenous cortisol, and the cellular response to cortisol. Compared to that of well-nourished children, those who are malnourished elicit a Th2-dominated response during stress, and both their basic cortisol and their rise in plasma cortisol are enhanced.27 Furthermore, the amount of GC–receptor complex that reaches the nucleus and mediates the GC response is increased in malnourished children, even if the cytoplasmatic membrane GC–receptor levels do not differ from those of well-nourished controls.27

Alexander Kinlen43 and Mel Greaves44 have presented the two most prominent hypotheses for the association between childhood infections and risk of childhood ALL.43, 44 According to Kinlen's43 population mixing hypothesis, the childhood ALL incidence increases both among the immigrants into a geographical region and among the region's original residents as a result of exposure to previously unencountered infections, which leads to lymphoproliferative stress.43 As an alternative, although compatible with the population mixing hypothesis, Mel Greaves'44 two-hit or delayed infections hypothesis proposes that common childhood ALL arises as a consequence of at least two independent mutations. One of these arises in utero, and if the children experience limited exposures to bacterial and viral infections in the first year of life, the risk of subsequent mutation(s) that lead to ALL will increase, as the immune system is improperly developed, and thus elicits an abnormal proliferative response.44 However, the search for specific postnatal leukemogenic infectious agents has been unsuccessful.

Kinlen's43 and Greaves'44 hypotheses are both compatible with the adrenal hypothesis, which proposes that early infections affect childhood ALL risk by a direct antileukemic effect of cortisol and by its modification of the Th1/Th2 balance.28, 45 At birth, humoral and cellular immunity, the Th1/Th2 balance and the hypothalamus–pituitary–adrenal axis are relatively immature.41, 42, 46 The types and severity of infectious disease burden in early life can influence the extent to which subsequent childhood infections elicit a Th1 (proinflammatory) response.47 Thus, the immune system may adapt to the high infectious burden in developing countries to avoid an overreactive inflammatory response induced by Th1 cytokines (IL-1, IL-12, tumor necrosis factor-alpha and interferon-gamma), as this may be severe and life-threatening, not least in a malnourished child.48 Cortisol favors the production of the anti-inflammatory Th2 cytokines such as IL-4 and IL-10 (an IL-12 inhibitor), and can prevent the damaging and proliferative stress of the proinflammatory Th1 cytokines by acting directly on T cells or indirectly by inhibiting IL-12 production by monocytes.28, 49 Although it remains to be proven in humans, animal models have shown that intense stimulation of the immune system early in life with Gram-negative bacterial endotoxins induces permanent changes in the immune response with subsequent more sustained rises in plasma cortisol at later stress and more suppression of lymphocyte proliferation.50

The adrenal hypothesis proposes qualitative and quantitative changes in the hypothalamus–pituitary–adrenal axis that explain several of the observations on which Alexander Kinlen43 and Mel Greaves44 have founded their etiological hypotheses on childhood ALL. Still, many issues relating to the adrenal hypothesis remain to be addressed. Among others, these include (i) further studies of the incidence and prevalence of children born with preleukemic cells in developed and developing countries; (ii) the subsequent kinetics of presumed disappearance of preleukemic cells in healthy children in relation to the pattern of early childhood infections; and (iii) comparisons of the ACTH response of healthy children in relation to their infectious history. Such studies will increase our understanding of the natural history of common childhood ALL, which eventually could lead to preventive measures.


K Schmiegelow1,2, T Vestergaard1, S M Nielsen1 and H Hjalgrim3

1. The Pediatric Clinic, The University Hospital Rigshospitalet, Copenhagen, Denmark
2. The Medical Faculty, The Institute of Gynecology, Obstetrics, and Pediatrics, The University of Copenhagen, Copenhagen, Denmark
3. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

Correspondence: Professor K Schmiegelow, The Pediatric Clinic, JMC-5704, University Hospital Rigshopspitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail: kschmiegelow@rh.dk



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