The 47th Bubble Wrap

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With millions upon millions of journal articles being published every year it is impossible to keep up.  Every month we ask some of our friends from PERUKI (Paediatric Emergency Research in UK and Ireland) to point out something that has caught their eye.

Article 1: The safety profile of ceftriaxone

Zeng, L., Wang, C., et al., (2020) Safety of ceftriaxone in paediatrics: a systematic review. Archives of Disease in Childhood. Oct;105(10):981-985. doi: 10.1136/archdischild-2019-317950

What’s it about? 

Ceftriaxone is one of the most commonly prescribed antibiotics for children. It is a broad spectrum third generation cephalosporin, used as a first line empirical agent for meningitis, sepsis and useful against many bacterial infections. It has an elimination half-life of 8 hours and can be given once every 24 hours IV or IM, giving us options when that cannula is particularly tricky! Whilst it is well known that using ceftriaxone in the newborn is contraindicated due to biliary sludging, the authors of this paper delved into the literature to identify other adverse reactions (ADRs) to ceftriaxone.

What did they do?

The authors performed systematic searches across several databases looking for studies to evaluate the type of ADR, the incidence of ADRs in patients aged 0 – 18 years old and to identify any potential risk factors for serious ADRs. A total of 112 studies were identified (22 RCTs, 61 case reports, 19 prospective studies, 7 retrospective studies, 2 case series and 1 case control study) which reported on ADRs of ceftriaxone use (although it was not a primary outcome measurement in any of the studies).

Looking at the RCTs, prospective and retrospective studies, gastrointestinal side effects were the most common ADR (specifically, diarrhoea). The second most common ADR identified amongst these studies was hepatobiliary (biliary sludging and cholelithiasis). These ADRs were all transient, and usually self-resolved after cessation of ceftriaxone. The case reports and case studies identified the more serious ADR of immune haemolytic anaemia, which carries a risk of death, especially for patients with an underlying diagnosis of sickle cell disease.

Clinically Relevant Bottom Line:

Transient gastrointestinal side effects are generally tolerable, and we should closely monitor patients for evolving symptoms of gallstones. Most importantly, we should be mindful and cautious when prescribing ceftriaxone in patients with underlying haematological conditions such as sickle cell anaemia, due to the uncommon but significant risk of immune haemolytic anaemia. Ceftriaxone is really a great antibiotic, and as long as we remember the clinical spectrum of ADRs, we will not cause significant patient harm.

Reviewed by: Tina Abi Abdallah

Article 2: Kawasaki Disease vs Septic Shock: Early Differentiating Features Despite Overlapping Clinical Profiles

Power A, Runeckles K, Manlhiot C, Dragulescu A, Guerguerian AM, McCrindle BW. Kawasaki Disease Shock Syndrome Versus Septic Shock: Early Differentiating Features Despite Overlapping Clinical Profiles. J Pediatr. 2020 Dec 5:S0022-3476(20)31482-7. doi: 10.1016/j.jpeds.2020.12.002. Epub ahead of print. PMID: 33290811.

What’s it about? 

According to literature around 6-7% *of patients with Kawasaki disease present with shock and this can provide a challenge in differentiating Kawasaki disease from septic shock. This paper looks to compare clinical features, resuscitative measures and haemodynamic response to treatment between those presenting with Kawasaki disease shock syndrome and children with septic shock.

*Kanegaye JT, Wilder MS, Molkara D, Frazer JR, Pancheri J, Tremoulet AH, et al. Recognition of a Kawasaki Disease Shock Syndrome. Pediatrics 2009;123:e783-9.

What did they do?

This was a retrospective chart review of patients under the age of 18 over a 10-year period admitted to a tertiary centre in the USA. The charts of children who met the criteria for Kawasaki disease shock syndrome (as defined by the American Heart Association) were analysed and children meeting the criteria for septic shock were used as controls. Over the 10-year period >1000 children were admitted to the centre with Kawasaki disease. Of these 9 met the criteria for Kawasaki disease shock syndrome. They were case matched with 18 controls who were admitted with septic shock.

The study found that children with Kawasaki disease shock syndrome were less likely (1 in 9) to have an underlying significant medical illness than the septic shock group (11 in 18). All the patients in the Kawasaki group had at least one of the five classic features of Kawasaki disease at presentation (rash, conjunctivitis, mucous membrane changes, cervical lymphadenopathy and extremity changes). With rash found in 7 of 9 of the patients either at presentation or during the admission. 5 in 9 of the Kawasaki disease cohort had cardiac involvement with zero of the control group with any cardiac involvement.

The length of stay for children in the Kawasaki disease shock syndrome group was a median of 9 days vs 28 days in the septic shock group, with no difference found in ICU length of stay. Biochemical markers were compared, and this study found a lower platelet count (median 140 vs 258) in the Kawasaki group. Interestingly in children with Kawasaki disease shock syndrome the duration of illness prior to admission was much longer (9 days vs 3 days) than the control group.

There have been no studies that directly compare children with Kawasaki disease shock syndrome and septic shock, so this acts as a starting point. However, it is a very small cohort (only 9 patients out of >1000 presentations of Kawasaki disease with Kawasaki shock syndrome); perhaps a multi- centre trial within a network could be done to increase the numbers.

Clinically Relevant Bottom Line:

This study has found that when compared to children with septic shock children with Kawasaki disease shock syndrome are more likely to have a lower platelet count on admission, a longer duration of illness prior to admission, cardiac involvement if an echo is performed and have a longer stay in hospital. All the patients in this study had at least one of the classic features of Kawasaki disease with rash being the most common here. As clinicians who review these children at the front door perhaps a child with a rash and low platelets fever >5 days will continue to make us think about Kawasaki disease.

Reviewed by: Vicki Currie

Article 3: Is it necessary to evaluate urinary tract infection in children with lower respiratory tract infection?

Kim JM, Koo JW, Kim H-B. Is it necessary to evaluate urinary tract infection in children with lower respiratory tract infection? Journal of Paediatrics and Child Health. 2020 Dec;56(12):1924-1928

What’s it all about?

Lower respiratory tract infections (LRTIs) and urinary tract infections (UTIs) are common childhood infections that previous literature has reported to have a concomitance rate of 3 to 10 per 100 children. While LRTIs are often self-limiting viral infections, UTIs are often caused by a bacterial source that can have long term implications if not adequately treated.

What did they do?

This was a retrospective review of 1574 patients’ medical records under 36 months of age who were hospitalised for a LRTI over a 2 year period in a South Korean hospital. 278 of patients had a fever and underwent a subsequent urine evaluation performed either by catheterisation (<24mo) or voided urine (24-36mo).

Patients with a congenital airway or kidney disease, absence of fever at presentation or whose parents refused or failed to undergo a urinalysis were excluded from the analysis.

The overall prevalence rate of a concomitant UTI with LRTI in this population was 1 in 10 in children <36mo and 13 in 100 in children <24mo. Mean age was significantly younger in the UTI group 7 months vs 12 months in the non UTI group. There was a greater prevalence rate of UTIs in boys (n=23) compared to girls (n=7). The most common organism cultured in the UTI group was Escherichia coli which were all treated with a third-generation cephalosporin. The positive rate of virus detection was 93.3% in the UTI group, and 89.9% in the non-UTI group. Most frequently detected co-infections were adenovirus, rhinovirus, and RSV.

The Bottom Line:

LRTIs and UTIs are common childhood infections that have up to a 1 in 10 concomitance rate.  A child presenting with a LRTI and concomitant UTI may present to ED with early respiratory and non-specific symptoms of a UTI (fever, lethargy and irritability), which may lead clinicians to presume a respiratory source of infection and not perform or delay a urinalysis. Hence a diagnosis of an underlying UTI may be missed. Failure to diagnose and promptly treat an underlying UTI can lead to renal morbidity including renal scars, hypertension and chronic kidney disease. Considering the ease of diagnosing and treating a UTI, this study further reiterates the importance of excluding a UTI in children with LRTIs under 36 months of age, especially of male gender. However, given the nature of this single centre study in South Korea, these findings cannot be generalised to a global population and must be taken in context to the population you encounter in clinical practice.

Reviewed by: Emma Chan

Article 4: Why don’t kids get sick with COVID-19?

Zimmermann P, Curtis N., Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections Arch Dis Child 2020;0 1-11

What’s it about?

A review article analyzing the possible mechanisms for reduced severity of COVID-19 in paediatric patients. The debate about if children have a lower rate of COVID-19 infection continues but it is known that children are less severely affected (in contrast to other respiratory viruses). This appears to be true even in paediatric patients with immune suppression or preexisting conditions e.g. IDDM. What we don’t know is why. The authors look at the evidence for multiple hypotheses but the two they favor are:

1)     Age related endothelial damage and increased coagulability. This fits the clinical profile of COVID-19 which features endotheliitis, micro thrombi, thrombotic complications and vasculitic skin manifestations. It could also explain COVID-19 being more severe in conditions which damage the endothelium e.g. hypertension and diabetes.

2)     Age related changes to the immune system. There is a decline in innate and adaptive immunity in the elderly compared with children who have not gone through this decline. The chronic proinflammatory state (which predisposes to the cytokine storm seen in severe COVID-19) increases with age. Additionally the authors hypothesize that the effect of chronic CMV infection on T-cells may explain the worsening of COVID-19 with age.

The authors concluded that these were the only two hypotheses which fit with the age-gradient in COVID-19 with mortality and morbidity rising steeply after 60-70.

The bottom line

If we could figure the ‘magic formula’ protecting children against severe COVID-19 we could use this to target treatment in adults. However, this paper is very much exploring theories and cannot yet be extended to clinical treatments.

The interplay between a lack of endothelial damage, lack of propensity to hyper-coagulation and their not yet declined immune system are most likely to protect children from severe COVID-19 infection.

Reviewed by: Sarah Reynolds

Article 5: A Gut Feeling: Abdominal Symptoms as an Initial Presentation of EVALI

Christel Wekon-Kemeni, MD, Prathipa Santhanam, MD, Pallav Halani, MD, Lauren Bradford, MD, Ceila E. Loughlin, MD.A Gut Feeling: Abdominal Symptoms as an initial presentation of EVALI, Paediatrics Volume 147, number 1, January 2021.

What’s it about?

 

Vaping or electronic cigarette use associated lung injury (EVALI) is a syndrome resulting from electronic cigarette use which causes predominantly respiratory symptoms, such as shortness of breath.

This case report describes an American 13-year-old male presenting, on two occasions primarily with abdominal symptoms of pain, nausea and vomiting. Initially, he was managed as a case of gastroenteritis, and had been noted to have borderline saturations. Initial abdominal CT report described bilateral lung pathology (lower lobe consolidation and atelectasis) in addition to mild jejunal loop thickening. However, after a second admission with similar symptoms plus raised inflammatory markers and fever, further workup was commenced. 

Repeat abdominal CT excluded appendicitis and evidence of inflammatory bowel disease. CXR revealed bilateral changes and a Thoracic CT identified multifocal ground-glass changes and infiltrates bilaterally with scattered septal thickening and dependent bibasal opacities.

Following a review of the patient by the respiratory team, a year long history of e -cigarette use preceding this patient’s symptoms was discovered, identifying EVALI as the potential diagnosis.

The patient was started on intravenous methylprednisolone which, following an improvement in all symptoms, was converted to a  course of oral corticosteroids. Repeat thoracic CT one month following discharge showed almost complete resolution of the initial changes. 

Why does it matter?

EVALI is a relatively new syndrome, mostly documented in North America, with the potential to increase in prevalence as we see the popularity of e-cigarette use continuing to rise.

Given this patient’s initial symptoms of nausea and vomiting, detailed smoking history to include e-cigarette use may not have been taken. Thus, a workup for abdominal pathology was justifiably completed. However, considering published case reports of EVALI describing nausea and vomiting as common symptoms, this diagnosis should still be considered in patients presenting without respiratory involvement initially. The data available describing EVALI in the paediatric population is sparse, nevertheless in adult’s progression to respiratory failure requiring invasive ventilatory support is reported.

Clinically Relevant Bottom Line:

 Although challenging, obtaining an accurate smoking history to include e-cigarette use in young people is important for the consideration of EVALI as a diagnosis. We still don’t completely understand the pathophysiology of e-cigarettes, or how much damage they are causing to the young people we see who smoke them, but remembering to ask about this as part of your history is a step we can take to improve knowledge and understanding.

Reviewed by: Joshua Tulley

If we have missed out on something useful or you think other articles are absolutely worth sharing, please add them in the comments!

That’s it for this month. Many thanks to all of our reviewers who have taken the time to scour the literature so you don’t have to.

About the authors

  • Vicki is a Paediatric Registrar in the West Midlands in the UK , starting PEM in September 2021. Vicki is passionate about good communication in teams and with patients along with teaching at undergraduate and postgraduate level. When not editing Bubble wrap Vicki can be found running with her cocker spaniel Scramble or endlessly chatting with friends.

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