A step-by-step approach to paediatric neutropenia

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Author's Personal Copy SYMPOSIUM: HAEMATOLOGY

A step-by-step approach to paediatric neutropenia

they bind to pathogens, release their toxic granules, and phagocytose foreign materials, including bacteria. Neutrophils have a short half-life once in the circulation, remaining there only 7e12 hours before undergoing apoptosis. The circulatory half-life shortens further during infective episodes but is increased in the tissues to enhance microbial killing. The combination of a short circulatory half-life and rapid migration of activated neutrophils can result in neutropenia during an infective episode. This is particularly so where the storage pool is reduced and there is an inadequate boost to neutrophil production, such as occurs with a hypoplastic bone marrow, e.g. Fanconi Anaemia, post chemotherapy. Similarly, neonates can become neutropenic because the storage pool is limited and production is already near maximal. However, the neutropenia may be the primary problem that then increases the risk of infection. Although initial treatment will be the same, if the neutrophil count does not recover once the infection is adequately treated, this should prompt further investigation to determine the underlying cause.

Angela E Thomas Lesley A Simpson

Abstract Neutropenia is a common laboratory finding in children. The aetiology varies from benign transient post-viral suppression to overwhelming systemic disease. For medical providers, identification of the aetiology of neutropenia can be difficult, but clarification of the cause is important for determining management and prognosis. Neutropenia in children may be discovered during evaluation of a fever or illness, or may be found incidentally when a full blood count is undertaken for other reasons. It may be an isolated finding or may be associated with suppression of other cell lines. It is important to distinguish between transient or benign causes and severe congenital neutropenia or neutropenia associated with serious haematological or systemic disease. Appropriate advice and treatment must be given while further assessment and investigation take place. In this review, we will discuss how and where patients may present, initial management and investigation and when and with what urgency to refer to specialty care.

What is a normal neutrophil count? Neutropenia is defined as a reduction in the number of neutrophils in the peripheral blood when compared to age, sex and race matched healthy populations. Appropriate reference ranges are important to avoid misdiagnosing a child with neutropenia. Relative to white Caucasians, people of African, Afro-Caribbean, and Arabic decent have lower neutrophil counts; up to 25% of people of African descent have neutrophil counts of less than 1.0 109/litre. This ‘ethnic neutropenia’ tends to be benign, in that these individuals do not show increased rates of infection and further investigations are not generally necessary. However, if accompanied by recurrent infection or other significant symptoms and signs, further consideration of cause is warranted. Similarly, for infants the lower limit of normal is 1.0 109/litre, and children prior to onset of puberty tend to have neutrophil counts lower than adults. Neutropenia secondary to artefact is uncommon and may be due to white cell aggregation or agglutination, a clot in the specimen, an improperly stored sample, or one that is more than 72 hours old. Morphological review of a blood film is essential in the evaluation of neutropenia to pick up both artefact and pathology. A repeat full blood count, especially if the neutropenia is unexpected, is important to confirm the low count before undertaking further investigation. In all cases, clinical circumstances should guide interpretation of the results. Laboratory reference ranges should be stratified for age and where appropriate ethnicity. The severity and persistence of neutropenia can help predict the risk and severity of bacterial infection. Aetiology of the neutropenia is also important, as the risk is higher in those conditions where production is reduced rather than consumption or destruction increased. Neutropenia is mild and the risk of infection low if the absolute number is below the lower limit of normal but more than 1.0 109/litre. Risk is increased for moderate neutropenia with counts between 0.5e1.0 109/litre. For those in the severe and very severe range, 0.2 less than 0.5 109/litre and less than 0.2 109/litre respectively, the risk of life-threatening infection is significantly increased, particularly if the neutropenia persists more than a few days.

Keywords aetiology; investigation; neutropenia; paediatrics

What is the role of the neutrophil? Most haematopoiesis takes place in the bone marrow and involves exposure of pluripotent stem cells to multiple growth factors in sequence. White blood cells are generally classified into myeloid (granular) and lymphoid and monocytic (agranular) cells. Stem cells that differentiate into myeloid cells mature sequentially from myeloblasts to polymorphonuclear cells (PMNs), which further differentiate to neutrophils, basophils, or eosinophils. Neutrophils make up the majority of circulating white blood cells and play a critical role in innate immunity. PMNs collectively respond to infection, allergic reactions and inflammation. As the neutrophil is the prime responder to infection, patients with neutropenia are at increased risk of bacterial and fungal infections. Once a neutrophil leaves the bone marrow, it enters the circulation from where it can be rapidly recruited to sites of inflammation or injury. Neutrophils first roll along and then adhere to vascular endothelial surfaces. They then move through endothelial junctions (diapedesis) and migrate to extravascular sites of inflammation, tissue injury or infection. Once recruited,

Angela E Thomas MB BS PhD FRCPE FRCPath FRCPCH is a Consultant Paediatric Haematologist in the Department of Haematology, Royal Hospital for Sick Children, Edinburgh, UK. Lesley A Simpson MD is a Consultant Paediatric Haematologist and Oncologist in the Department of Haematology, Royal Hospital for Sick Children, Edinburgh, UK.

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is there a history of recent viral or recurrent or unusual bacterial infection? how long have any symptoms been present? has there been any drug exposure, accidental or prescribed? is there a family history of recurrent infection or unexplained infant death? are any constitutional or systemic symptoms such as fatigue, joint pain or a limp present? Important points to note in the examination: is there mucositis, buccal ulceration, gingivitis or poor dental health? is there evidence of infection: skin, upper respiratory tract, pneumonia? are perineal or perirectal lesions or fissures present? is there evidence of short stature or microcephaly? are there any skeletal, skin or nail abnormalities? is there any bruising or bleeding? is lymphadenopathy or hepatosplenomegaly present? These points are summarised in Table 1. If the child is unwell, whether or not there are signs of constitutional or systemic disease, immediate referral to the hospital is mandatory. The presence of neutropenia and a limp or bone pain is a typical presentation of acute leukaemia. If neutropenia secondary to drug exposure is suspected, the drug should be discontinued immediately and the child referred promptly to a specialist for close monitoring and assessment. Excluding cytotoxic chemotherapy, such medication reactions tend to be idiosyncratic and are rare. They are either immunemediated or due to direct myeloid toxicity leading to agranulocytosis, the latter being associated with significant infectious

What are the important features in the history and physical examination? Individuals may present before neutropenia has been identified. They may be acutely unwell, mildly unwell or asymptomatic. A child can present at any age, but congenital neutropenia is more likely in a young infant than an older child. Patients may present to their general practitioner or to hospital, and the scenarios are likely to be different depending on where the patient presents. If the child is known to have neutropenia, then presentation is most likely to be precipitated by a fever. Neutropenia may be chronic or acute and symptoms and signs will differ. For those with chronic severe neutropenia, symptoms and signs such as recurrent oral disease, poor dental health and perineal problems are seen. There may be a history of recurrent or unusual infections, including fungal infection such as oral thrush. Acute neutropenia, if severe, usually presents with a febrile illness, with or without an obvious focus of infection. Figure 1 shows an algorithm for management and investigation of neutropenia.

Presentation to a general practitioner A child with undiagnosed neutropenia may present to their general practitioner (GP) not acutely unwell, the neutropenia only becoming apparent once a full blood count has been processed. Symptoms may include coryza, cough or fever, recurrent infection and mouth ulcers, but many children with mild neutropenia are asymptomatic. A repeat count should taken, which may be at the GP surgery or at the local hospital. Important points to note in the history: have any previous blood counts shown a normal neutrophil count?

Isolated Neutropenia?

Yes Yes

Acutely unwell or febrile?

Admit for IV antibiotics and evaluation

No Recent medication exposure?

Yes

Stop medication immediately; refer to specialist for assessment and close monitoring

Yes

Refer to specialist to rule out congenital neutropenia, haematological disorder or systemic autoimmune disease. Urgency depends on clinical condition

No History of frequent or unusual bacterial infection?

No Symptoms of systemic disease or syndromic features?

Yes If neutropenia persists

No Yes

Repeat weekly up to 4–6 weeks until resolution

Recent viral illness?

No Ethnic background with lower ‘normal’ levels?

Yes

Reassurance

No Probable Benign/ Autoimmune Neutropenia

Yes

Routine referral for consultation Neutrophil antibody testing may be helpful

Figure 1 Algorithm: initial investigation and management of neutropenia.


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skeletal abnormalities such as abnormal thumbs, short limbs abnormal skin pigmentation

Important points in history and examination in a neutropenic child History Previous full blood count available Recent viral infection Medications Other constitutional symptoms Family history Neutropenia Frequent or unusual infections Physical examination Height, weight Head circumference Skeletal, skin, or nail abnormalities Skin infections Mucositis/ulcers/gingivitis/ dental health

Investigations All or some of these may be performed, guided by the full blood count results and clinical findings. Neutrophil antibodies if positive, this supports a diagnosis of autoimmune neutropenia of childhood. This test has a high positive predictive value, but is insensitive and false negatives are common. B12 and folate levels particularly if there are other cytopenias or the MCV is raised immunoglobulin levels T and B cell subsets direct antiglobulin test viral screen (including HIV) may be helpful amino and organic acid testing especially neonates or infants with hypoglycaemia or neurological symptoms Once immune deficiency has been ruled out, a child with neutropenia may proceed or continue with the routine childhood vaccination schedule.

Age at first infection Frequency of infections Severity of infections Sites of infections

Autoimmune disease Early infant death from infection Perineal or perirectal lesions or fissures Upper respiratory tract infections Bruising or bleeding Hepatomegaly or splenomegaly Lymphadenopathy

Table 1

Presentation to the Accident and Emergency Department

complications and a mortality rate of 5e10%. Offending medications include anti-thyroid drugs, antimicrobials, anticonvulsants, and antipsychotics. If the child is well, history and examination are unremarkable, and there is no exposure to medication, a full blood count should be repeated on several occasions over a period of weeks. Neutropenia secondary to viral infections should resolve within 4e6 weeks but if it fails to do so, referral to a specialist is appropriate. During this time, parents or carers should be advised that if their child becomes febrile or unwell, they should seek medical advice urgently, which in practice usually means presentation to the local Accident and Emergency Department. This advice should be clearly documented in the medical notes and it can be helpful to give written information to the family.

When a child with known neutropenia is unwell or presents with a suspected acute bacterial infection, blood, urine, and respiratory cultures should be taken and treatment with broad-spectrum antibiotics started without delay. Choice of antibiotic should be informed by local microbiology policy. It is important to note that symptoms and signs of local infection are less evident in children with neutropenia, because without neutrophils, pus does not form. If neutropenia only becomes apparent at the time of presentation, initial clinical management is the same. Investigations should proceed if the neutropenia does not resolve or signs suggestive of causative systemic disease are present. In those who have other cytopenias, significant constitutional symptoms, or bone pain, leukaemia needs to be excluded. A bone marrow aspirate should be performed and marrow sent for chromosome studies, molecular analysis, and flow cytometry. The presence of a skin rash, joint swelling or pain, or symptoms of venous thrombosis suggests collagen vascular disease and an autoimmune screen should be undertaken. Specific features of congenital disorders of bone marrow should be actively sought and appropriate investigations initiated (Table 2).

Out patient referral Following our suggested algorithm (Figure 1), a patient may be referred (a) after persistent neutropenia has been established, (b) soon after it has been identified, particularly if there is a history of chronic neutropenia or concerning associated findings or (c) there is a history of frequent or unusual bacterial infection but the child is not acutely unwell. The same specific points in the history and examination as above should be noted (Table 1). It is important to establish how long the symptoms have been present and the frequency and severity of infections. There may be a history of the periodicity seen in cyclical neutropenia (see below). Repeated counts twice or three times weekly over 6e8 weeks may be necessary to document a cyclical pattern. Specific features to look for in syndromes associated with neutropenia are shown in Table 2 and include: short stature microcephaly


What causes neutropenia? Neutropenia can be due to intrinsic defects of the white blood cell, which are very rare, or to extrinsic factors, which may result in decreased bone marrow production or increased peripheral blood destruction and which are much more common. A congenital, intrinsic problem would tend to manifest in early life, sometimes as part of a syndrome, and usually with serious, recurrent or unusual infections. Acquired, extrinsic problems can occur at any age in previously healthy children. The causes of neutropenia in

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Causes of neutropenia Intrinsic/congenital neutropenia Disorder Cyclic neutropenia Severe congenital neutropenia including Kostmann’s syndrome

Inheritance AD Sporadic AR

SchwachmaneDiamond syndrome

AR

Dyskeratosis congenita

X-linked recessive AD AR

Reticular dysgenesis

AR

ChediakeHigashi syndrome

AR

Fanconi anaemia

AR

Extrinsic/acquired neutropenia Cause Post infectious Drug-induced

Associated features Infection with 21-day periodicity 50% mutations in ELA2 Severe infection from birth Neutrophils