It’s 4.30 pm and you have just seen a snotty, febrile, 2-year-old girl. At first, it seemed like a straightforward case of an upper respiratory tract infection until her mother mentioned that she had just come from phlebotomy for her daughter’s follow-up blood test for a previous neutrophil count of 0.7.
All these thoughts start running through your head: Is she still neutropenic? What caused her neutropenia? Could this be neutropenic sepsis? Has the paediatric haematologist already gone home? And will the outpatient bloods ever make it to the lab today?
You attempt to find a guideline, but struggle to locate a clear one for immunocompetent children. Like others, you start to think that there isn’t a single approach, and instead, we should consider the underlying cause and the likelihood of a serious infection.
What is the cause of the neutropenia?
Neutropenia : < 1.5×10^9 /l
Mild: 1.0×109 /l to 1.5×10^9 /l
Moderate: 0.5×109 /l and 1.0×10^9 /l
Severe: < 0.5×10^9 /l
The most common causes of neutropenia in well-appearing children over 3 months are viral illnesses and common bacterial infections. These, as well as drug-induced, B12 and folate deficiency, and autoimmune neutropenia, are thought to carry a low risk for serious bacterial infection.
Severe congenital neutropenia, cyclic neutropenia and Shwachman-Diamond syndrome are thought to be associated with a higher risk of invasive bacterial infections.
Individuals of African or Caribbean heritage may have a baseline neutrophil count between 1.0 and 1.5 × 10⁹/L. In mild cases, it is important to review normal reference ranges for different age groups and ethnicities, where available.
Let’s delve into the history
A thorough history is essential to identify underlying conditions that may increase a child’s susceptibility to infections. Key factors to explore include a history of serious or recurrent infections, frequent mouth ulcers or abscesses, multiple courses of antibiotics, and neonatal infections. It is also important to remain alert for red flags that could indicate an undiagnosed malignancy.
Review drug history in terms of immunosuppressant therapy within the last 6 months. The use of anticonvulsants and recent antibiotics may point to a drug-induced cause.
An incomplete vaccination history may identify vulnerability to certain pathogens.
A family history of autoimmune diseases, recurrent infections or immunodeficiencies may indicate a hereditary cause.
Onto the examination
Assess the child’s height and weight, as short stature can be associated with congenital neutropenia.
Examine the mouth for signs of gingivitis, which may suggest chronic neutropenia. If your membership exams are fresh in your mind, you might recall that leukoplakia can be a feature of dyskeratosis congenita. Similarly, the presence of skeletal abnormalities or dysmorphic features may point towards rarer causes of neutropenia, such as Shwachman–Diamond syndrome or Fanconi anaemia. A thorough, structured physical examination — including assessment of the HEENT region, lymph nodes, abdomen (for hepatosplenomegaly), and skin — is essential to ensure subtle signs are not missed.
Other concerning features, such as diffuse lymphadenopathy or hepatosplenomegaly, may suggest an underlying malignancy.
Your clinical examination will help determine the likely cause of the fever and guide decisions on whether antibiotics are required. Look for risk factors for serious bacterial infection (SBI), such as indwelling catheters or other intravascular devices. Don’t forget to ensure that a complete set of observations has been recorded, and that you have carefully assessed and reviewed for any signs of sepsis.
Initial investigations
According to NICE guidelines, a blood film should be requested in all patients with neutropenia. It is also important to consider the degree of neutropenia, as this can guide the urgency of investigations and management. Other findings within the full blood count (FBC) may provide diagnostic clues. Additional tests such as liver function tests, folate, and vitamin B12 levels can help identify potential underlying causes.
Features of blood film:
- Severe congenital neutropenia: increase in monocytes, basophils or eosinophils
- Viral infection: atypical lymphocytes
- Bone marrow failure or infiltration: anaemia and/or thrombocytopenia. Presence of blasts
- Bacterial sepsis: toxic neutrophils
You take this approach and find this 2-year-old is normally well, only had one course of antibiotics for an otitis media last year and has no significant family history.
So, what should we do next? What’s the evidence?
“A few older retrospective studies have explored the incidence of serious bacterial infections (SBIs) in immunocompetent children. Interestingly, Barb et al. reported that SBIs were more common in the control group (26%) compared with the neutropenic group (8%). However, this study has several limitations. The method of control group selection was not clearly described, making it difficult to rule out selection bias. Furthermore, SBIs were defined as either a positive culture or a radiological finding on a chest x-ray, but not all children underwent these investigations, introducing the possibility of a type I error.
Melendez et al. conducted a larger retrospective study involving 1,888 neutropenic cases presenting to the emergency department. The incidence of SBI was highest in infants under 3 months old (3%), with an overall incidence of 2.2%. However, the investigations performed varied between cases, and only 70% of patients had at least one culture taken, raising the possibility of missed SBIs. Fever was not an inclusion criterion for the study, and there was limited information regarding the clinical presentation of these patients.
Pascual et al. focused exclusively on febrile children with moderate or severe neutropenia. Interestingly, nearly half of these patients were admitted for treatment with broad-spectrum antibiotics. An infectious agent was identified in 12% of cases, and of these, 91% were viral. Only 2% had a confirmed SBI, which included two cases of urinary tract infection and two cases of pneumonia.
A more recent retrospective study of 82 patients with severe neutropenia found no cases of invasive bacteraemia. Only 1% were thought to have an actual urinary tract infection, and 2% were treated for possible pneumonia, although the chest x-ray findings were inconclusive. However, the small sample size limits the generalisability of these findings, and 50% of patients had only a documented fever at home, which may have biased the cohort towards children who were less unwell at presentation.
Hao et al. conducted a systematic review which found that the incidence of SBI in well-appearing children with febrile moderate-to-severe neutropenia ranged from 2–8%. A meta-analysis could not be performed, underscoring the limitations of the retrospective studies included. The inclusion criteria and definitions of SBI varied between studies, and investigations were not consistently performed on all patients, making the true incidence of SBI difficult to determine. Furthermore, the reliance on positive culture results—known to be less than 100% sensitive—limits the accuracy of these findings. Importantly, these studies often failed to incorporate other markers of SBI, such as clinical signs of sepsis or inflammatory markers, into their analysis.
Takeaway message
The evidence for the management of febrile isolated neutropenia in an immunocompetent child is poor.
Low-level evidence has shown the incidence of SBI to be low, however management decisions should always be made in the context of the individual child.
References
Sung et al, Approach to febrile neutropenia in the general paediatric setting, Paediatr Child Health. 2007 Jan;12(1):19–21.
Lirette et al, Management of febrile neutropenia in immunocompetent children and youth, Canadian Paediatric society, Paediatr Child Health 28(5):324–326
Alexandropoulou et al. Transient neutropenia in children with febrile illness and associated infectious agents: 2 years’ follow-up. Eur J Pediatr 2013;172(6):811–19.
James et al, Fifteen-minute consultation: A guide to managing a child with a new finding of neutropenia, Arch Dis Child Educ Pract Ed 2019;104:282–285.
Paul Virgo, Children’s Reference Ranges for FBC, North Bristol NHS Trust, available, https://www.nbt.nhs.uk/sites/default/files/Childrens%20FBC%20Reference%20Ranges.pdf
NICE, Suspected sepsis: recognition, diagnosis and early management, NG 51, last updated 16 July 2016, available https://www.nice.org.uk/guidance/NG5
NICE, Neutropenic sepsis: prevention and management in people with cancer, Clinical guideline, Reference number: CG151 Published: 19 September 2012
Barb et al The risk of serious bacterial infection in neutropenic immunocompetent febrile children. J Pediatr Hematol Oncol 2015
Melendez et al Risk of Serious Bacterial Infection in Isolated and Unsuspected Neutropenia, Academic Emergency Medicine February 2010 , Volume 17 ( 2 ), p 163 – 167
Pascual et al, Outcomes and infectious etiologies of febrile neutropenia in non-immunocompromised children who present in an emergency department, Eur J Clin Microbiol Infect Disease 2016 Oct;35(10):1667-72.
Morin et al, Management and outcome of febrile neutropenia in admitted presumed immunocompetent patients with suspected viral illness, Paediatrics & Child Health, Volume 27, Issue 7, December 2022, Pages 408–413
Hao et al, The prevalence of serious bacterial infections in neutropenic immunocompetent febrile children, The American Journal of Emergency Medicine, Volume 45, July 2021, Pages 1-6
Alario et al, Risk of infectious complications in well-appearing children with transient neutropenia. Am J Dis Child. 1989;143:973–6.
