Recurrent abdominal pain and childhood asthma (I, IV)

In study I, recurrent abdominal pain was reported an independent risk factor for asthma at school age in the group of children that wheezed at least once during the two first years of life, whereas a significant association between asthma in the two first years of life and recurrent abdominal pain at age 12 years was observed in study IV. Asthma at age 12 years was also related to an increased risk of concurrent abdominal pain. However, after

adjustments for other allergy-related diseases under study (allergic rhinitis, eczema and food hypersensitivity), asthma did not remain significantly associated with abdominal pain at 12 years.

Both study I and study IV indicate an association between asthma and recurrent abdominal pain. However, the temporal association between the two conditions remains unclear.

Questions regarding recurrent abdominal pain were not available in the four and eight year the follow-ups, contributing to the difficulties evaluating temporality. In additional analyses in this thesis, recurrent abdominal pain remained an independent risk factor for school age asthma after restriction of analyses to children that wheezed at least three times in the two first years of life (Table 10 and 11, page 35-36). Since the majority of these children satisfied the definition of asthma at age two years (Table 9, page 34), recurrent abdominal pain in infancy may be a consequence of asthma and not a risk factor for developing asthma as suggested in study I. We also performed additional analyses investigating the relation

association between recurrent abdominal pain in the two first years of life and at age 12 years (p=0.009), the vast majority (86%) of children with parental reported recurrent abdominal pain during the two first years of life did not report recurrent abdominal pain at age 12 years.

Thus, this additional information is not useful for assessing temporality of recurrent abdominal pain.

Few previous studies have been able to address the temporal relation between recurrent abdominal pain and asthma especially in paediatric populations, and the existing results are conflicting. Two studies support the conclusion from study I, reporting recurrent abdominal pain to precede symptoms of asthma in children. One was a cohort study where a history of recurrent abdominal pain was significantly associated with wheeze and asthma up to age seven years but not thereafter¹¹³, the other a case-control study where the majority of asthmatics reported symptoms of recurrent abdominal pain having occurred before those of asthma⁵⁹. In contrast, a U.K. study following a national sample of children from age seven to eleven suggested that wheeze may precede abdominal pain⁵⁰. Two retrospective studies reported a significant increase in IBS (irritable bowel syndrome, a specific phenotype of abdominal pain¹³⁹) incidence among people who already had asthma^{53, 54}, which corresponds with the conclusion of study IV. However, clinical symptoms of atopic diseases including asthma were not sufficient for IBS occurrence in a selected group of children aged three to 13 years with severe allergy⁷⁹.

Regardless temporality, the higher than expected prevalence of concurrent abdominal pain observed in 12-year-olds with asthma (study IV) as well as in wheezing infants (study I) compared to asymptomatic children is supported by numerous studies48, 50, 53-62, 76, 77, 140

, whereof five include children. This relation emphasizes the potential role of a common pathogenetic origin or shared susceptibility to common factors.

There are several hypotheses regarding mutual mechanistic origins between recurrent abdominal pain/IBS and asthma. For example, a generalized abnormality of both bronchial and intestinal smooth muscle cells and/or a disturbance of smooth muscle regulation by the autonomic nervous system have been suggested, but results are conflicting58, 78, 141

. This could be a plausible explanation to the occurrence of wheeze and recurrent abdominal pain and relation to school age asthma in study I. However, no independent association remained between asthma and concurrent abdominal pain in the 12-year-olds after adjustment for other allergy-related diseases in study IV, indicating that there may be other explanations or that this mechanism is not sufficient.

infants¹⁴⁶. Moreover, the prevalence of GER is higher among asthmatic children compared to non-asthmatics and can provoke attacks of asthma¹⁴⁷, and the relation between GER and asthma is well recognized¹⁴⁸. Residual confounding by these abdominal pain-related comorbidities cannot be excluded in study I or IV due to lack of information.

Another hypothesis is that these conditions have a common underlying inflammatory

process⁵⁸, since the respiratory and gastrointestinal tracts have analogous mucosal-associated lymphoid tissue¹⁴⁹. This inflammation could result in barrier defects in the gastrointestinal tract, increasing the risk of disturbed motility and pain sensitivity^{67, 80}. Thus, the relation between wheeze and recurrent abdominal pain in infancy and asthma in study I as well as the significant association between asthma and concurrent abdominal pain at age 12 years could be due to a shared low-grade inflammation in the respiratory and gastrointestinal tract.

Furthermore, one study reported a lower risk of IBS onset among asthma patients with per oral corticosteroid medication which has systemic anti-inflammatory effects⁵³, although this was not confirmed in another study⁵⁴.

A relationship between inflammation and gut motility or visceral pain perception has been proposed^{70, 74}. Mast cells are central in allergic inflammation and cause hyperreactive airways in allergic asthma. An accumulation of activated mucosal mast cells in the gut have been observed in some IBS patients^{70, 74}. Mediators secreted by these mast cells may interact with sensory nerve endings and promote visceral hyperresponsiveness that lead to symptoms of recurrent abdominal pain/IBS⁷⁴. It is therefore plausible that a mutual immunologic

dysregulation could be part of the explanation of the association between asthma or wheeze and recurrent abdominal pain in study I and IV. However, before we can extend the “united airways” to the “united mucosa” more mechanistic studies are needed⁵⁶.

The question of whether recurrent abdominal pain should be considered a risk factor or a consequence of asthma remains to be answered. However, the finding of an increment in risk of abdominal pain with increasing number of allergy-related diseases in the 12-year-olds in study IV strengthens the hypothesis of a common immune dysregulation, maybe combined with a primary neuromuscular disorder producing both respiratory and gastrointestinal hyperresponsiveness.

In additional analyses, recurrent abdominal pain in infant non-wheezers showed elevated odds ratios for school age asthma although not statistically significant (Table 12, page 37).

These results are based on few cases and the hypothesis that symptoms of recurrent abdominal pain and infant wheeze originate from abnormal smooth muscle function in the bronchi and gut cannot be evaluated. Moreover, food hypersensitivity was an independent risk factor in non-wheezers but we cannot exclude that some parents reported this symptom due to recurrent abdominal pain. Croup-like cough and cough during activity were

significantly associated with asthma and bronchial hyperresponsiveness may cause cough.

example of the fact that asthma is more than wheeze. It is not unusual that asthma underlies symptoms of prolonged cough or diffuse tiredness in children.