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Childhood LRTI linked to nearly two-fold higher risk of premature adult respiratory-related death

17th March 2023

A childhood lower respiratory tract infection (LRTI) nearly doubles the risk of a premature adult respiratory-related death according to the findings of a life-spanning cohort study by UK researchers.

Chronic respiratory diseases are a leading cause of death and disability worldwide and in 2017, represented the third largest cause of mortality. Moreover, adverse factors affecting lung development during foetal life as well as in early childhood, decrease the attainment of maximal lung function and accelerate function decline in adulthood. Although researchers have speculated for some time that there is a direct casual link between acute lower respiratory infection in early childhood and conditions such as chronic bronchitis in adult life, an absence of longitudinal data, makes it difficult to provide greater clarity on the relationship between childhood respiratory infections and possible early deaths from a respiratory cause.

In the current study, researchers prospectively collected data from a nationally representative cohort of all single births among married women during 1 week in March, 1946, across England, Scotland and Wales with a review to evaluating the association between the presence of a LRTI during early childhood (age < 2 years) and death from respiratory disease from age 26 through 73 years.

Childhood LRTI and premature respiratory-related death

Researchers included a total of 3,589 participants, aged 26 years (51% male) and who were included in the analysis from 1972 onwards and followed-up for a median of 47.9 years.

After adjusting for several factors including adult smoking, among these 3,589 participants, 25% had an LRTI during early childhood, which nearly doubled their risk of premature death from a respiratory-related disease by age 73 (Hazard Ratio, HR = 1.93, 95% CI 1.10 – 3.37, p = 0.021). Furthermore, in subgroup analysis, there was no evidence that an early childhood LRTI increased the risk of circulatory, cancer, external, other-cause, or all-cause mortality.

The researchers also calculated that the population attributable risk of premature adult death from respiratory disease due to early childhood LRTI was 20·4% and which corresponded to an estimated 179, 188 excess and premature adult deaths across England and Wales between 1972 and 2019.

The authors concluded that a LRTI during early childhood was associated with almost a two times increased risk of premature adult death from respiratory disease and that it accounted for a fifth of all these deaths.

Allinson JP et al. Early childhood lower respiratory tract infection and premature adult death from respiratory disease in Great Britain: a national birth cohort study. Lancet 2023

Can procalcitonin levels determine which patients will benefit from azithromycin in lower RI? 

17th January 2023

Low procalcitonin levels in patients with a lower respiratory infection (RI) do not indicate those who might benefit from azithromycin

Low procalcitonin levels in patients with a non-pneumonia lower respiratory tract infection, fails to identify those who might benefit from azithromycin therapy according to the findings of a randomised trial by US researchers.

Antibiotics are commonly prescribed for acute respiratory infections, although most of these infections are viral in nature and for which antibiotics are ineffective. It is therefore necessary to implement strategies that are able to identify those patients unlikely to benefit from antibiotics, thus mitigating the development and spread of resistant pathogens. Procalcitonin is a peptide for which serum levels are believed to increase during bacterial, but not during viral, infections. In fact, procalcitonin levels have been shown to improve the accuracy of currently recommended approaches for the diagnosis of community-acquired pneumonia, thereby complementing clinical signs and symptoms. Normal human procalcitonin serum levels are less than 0.1 ng/ml, whereas if levels increase above 0.25 ng/ml, this may indicate the presence of a bacterial infection.

In the present study, US researchers hypothesised that in patients with a procalcitonin concentration of 0·25 ng/mL or less, a placebo would be just as good, i.e., non-inferior (in terms of clinical efficacy) to antibiotics such as azithromycin, in adults with suspected lower respiratory tract infection. The team recruited adults aged 18 years or older, with clinically suspected non-pneumonia lower respiratory tract infection and a low procalcitonin level (i.e., 0·25 ng/mL or less). These individuals were randomised 1:1 to either oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). The primary outcome was the efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 (assessed with several different measures) and the non-inferiority margin (to placebo) was set as a lower confidence interval of -12·5%.

Low procalcitonin and azithromycin outcomes
A total of 499 participants with a mean age of 52.3 years (35% female), all of whom had procalcitonin levels below 250 ng/ml, were included and randomised to azithromycin (249) or placebo.

A clinical improvement at day 5 was observed in 63% in the placebo group and 69%, in the azithromycin group (between-group difference -6%, 95% CI -15 to 2). As the lower confidence interval for this difference was numerically greater than –12·5%, it was not possible to conclude that there was non-inferiority for the placebo compared with azithromycin. This was despite there being no significant difference in the rates of any of the individual parameters comprising the primary outcome for clinical improvement. However, at day 11, clinical improvement was observed in 76% of the placebo group and 81% in the azithromycin group (between-group difference –4%, 95% CI –12 to 3). This time, since the lower confidence interval value was less than -12.5, non-inferiority for the placebo and azithromycin was demonstrated.

The authors concluded that it was not possible to confirm non-inferiority for a placebo and azithromycin in terms of clinical improvement at day 5 in adults with a lower respiratory tract infection and a low procalcitonin concentration. Consequently, it remained unclear whether antibiotics would be of benefit to such patients.

Tsalik EL et al. Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial. Lancet Infect Dis 2022