the Management of Neutropenia in Pediatric Age Groups

Table 3. Recommendations

A.   Diagnosis of neutropenia

Source Guideline

Recommendations

QoE

SoR

Definition of neutropenia

A.1. We recommend the use of the following definition of neutropenia in neonates, infants and children

EHA-EuNet-INNOCHRON 2023

The definition of neutropenia varies according to the patient’s ethnic origin and age.

Neonates:

•  At term neonates

Neutropenia is defined as an absolute neutrophil count (ANC) level of 2.5 x10*9/L for term/near-term neonates 72–240 hours following delivery.

•  In preterm newborns

Neutropenia is defined as an ANC level of 1.0 x10*9/L for preterm neonates.

Infants and Children

•      The widely accepted cutoff level of ANC for the definition of neutropenia in Caucasian newborns and infants up to the age of 1 year is 1.0 x10*9/L.

•      From the age of 1 year to adulthood the cutoff level for neutropenia is 1.5 x 10*9/L.

GPS

Classification of neutropenia

A.2.a. We recommend the use of the following classification of neutropenia according to severity

EHA-EuNet-INNOCHRON 2023

•   Neutropenia is classified as mild when ANC is between 1.0 and 1.5 x 10*9/L, moderate when ANC is 0.5 to 1.0 x 10*9/L, and severe when ANC is <0.5 x 10*9/L.

•   The term agranulocytosis is used for severe neutropenia with ANC <0.2 x 10*9/L.

GPS

A.2.b. We recommend the use of the following classification of neutropenia according to duration

EHA-EuNet-INNOCHRON 2023

•   Neutropenia is also characterized as acute or chronic depending on whether the duration is <3 or >3 months, respectively.

GPS

A.2.c. We recommend the use of the following classification of neutropenia according to etiology?

EHA-EuNet-INNOCHRON 2023

An extended, pathogenesis-based classification categorizes neutropenia as congenital versus acquired and likely acquired.

GPS

A.2.d. We recommend the use of the following congenital neutropenia definition and its classification?

EHA-EuNet-INNOCHRON 2023

•   Congenital neutropenia (CN) comprises a group of genetic diseases characterized by impaired production, differentiation, and survival of neutrophils in the bone marrow (BM), susceptibility to infections, and increased propensity to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) transformation.

•   CN can be further subclassified into disorders where neutropenia is the only abnormality and those where neutropenia is associated with extra-hematological manifestations, immunodeficiency/immune dysregulation, metabolic disorders and nutritional deficiencies, or as part of more complex BM failure syndromes.

•   The classification also takes into consideration the genes that have been identified as responsible for each CN subtype.

•   Individuals of African and Middle Eastern descent display normal ANCs in the range from 0.5 to 1.5 x10*9/L and less frequently even lower.

•   This variation, previously termed ethnic neutropenia, is usually inherited as an autosomal recessive trait associated with a polymorphism (rs2814778, −46T>C) in the GATA box in the promoter region of the atypical chemokine receptor-1 (ACKR1) gene, also known as the duffy antigen receptor for chemokines (DARC).

•   In homozygosity (C/C), the polymorphism results in the absence of Duffy antigen expression specifically on red blood cells, a phenotype known as Duffy-null.

•   The guideline working group suggests the introduction of the term ACKR1/DARC-associated neutropenia (ADAN), instead of ethnic neutropenia, to emphasize the genetic rather than the ethnic basis of this entity.

GPS

Causes of neutropenia

A.3.a. We recommend the use of the following causes of neutropenia in the neonatal period?

EHA-EuNet-INNOCHRON 2023

Examples of variables not related to pregnancy or delivery capable of interfering with the ANC are the following:

·      females have ANC counts on average 2.0 x 10*9/L higher than males.

·      ANC in capillary blood is on average 1.5–2.0 x10*9/L higher than in cord blood.

·      ANC is on average higher at altitude than at sea level.

·      Severe necrotizing enterocolitis in the newborn, especially if preterm, is frequently associated with transiently low ANCs.

Examples of variables related to pregnancy or delivery include the following:

·      maternal tobacco smoking is associated with lower ANC.

·      maternal chemotherapy results in neutropenia

·      maternal antiretroviral therapy results in neutropenia.

·      maternal hypertension during pregnancy results in neutropenia.

·      prenatal growth retardation is an independent risk factor for neutropenia.

·      Rh-hemolytic disease of the newborn is associated with neutropenia in about 50% of newborns whether or not combined with severe anemia and thrombocytopenia.

·      twin-twin transfusion syndrome is a rare condition with neutropenia always present in the donor twin (the anemic one).

·      neutropenia is present in 67% of infants with asphyxia.

GPS

A.3.b. What are the types of immune neutropenia specific to neonates?

EHA-EuNet-INNOCHRON 2023

Neonatal immune neutropenia can be subclassified as the following:

1.     AIN, which is unusual, but not impossible, at <1 month of Age.

2.     Neonatal alloimmune neutropenia (NAN) in which a genetic mismatch for a polymorphism in one of the genes encoding human neutrophil antigens (HNA) between mother and fetus leads to immunization of the pregnant woman, passage of alloantibodies over the placenta and neutropenia in the baby. Indirect antineutrophil antibodies are positive in the mother and in the newborn. The diagnostic confirmation may be obtained through a positive crossmatch between maternal sera and paternal granulocytes (even if not routinely indicated).

3.     NAN secondary to maternal AIN is the rarest immune neutropenia of early infancy. The duration of this neutropenia is on an average the same as the classic NAN.

GPS

A.3.c. What are the following causes of acquired neutropenia to be considered?

EHA-EuNet-INNOCHRON 2023

Consensus was reached to classify acquired neutropenia as primary or idiopathic, associated with the presence of antineutrophil antibodies or other unknown mechanisms; and secondary due to infections, autoimmune diseases, exposure to drugs, nutritional deficiencies, hypersplenism, or hematologic diseases.

GPS

Clinical diagnosis of neutropenia

A.4.a. What are the required points in history taking for patients presenting with neutropenia?

EHA-EuNet-INNOCHRON 2023

•   Patient history should include inquiry about occurrence of infections and their frequency, type, severity, and need for hospitalization. Specifically, history of omphalitis, gingivitis, periodontitis, skin infections, abscesses, and pneumonias as well as duration and response to antibiotics should be also investigated.

•   Presence of congenital malformations in the patient or family is important.

•   For adult patients, drug history is important, as well as work-up for autoimmune and other disorders that may be associated with neutropenia.

•   Detailed family history should include ethnic origin, consanguinity, occurrence of recurrent infections, and neutropenia in other family members, as well as unexplained infant death or miscarriages.

•   A detailed history should be taken of any symptoms denoting underlying autoimmune or other diseases that may result in secondary neutropenia.

•   History of chronic viral infections such as viral hepatitis or HIV should also be obtained.

•   Careful inquiry should be made concerning drug administration, including over the counter drugs, substances often denominated as natural supplements, and recreational drugs; neutropenia can be linked not only to drugs that the patient has recently started but also to drugs that have recently been discontinued.

GPS

A.4.b. What is the required detailed clinical examination in patients presenting with neutropenia?

EHA-EuNet-INNOCHRON 2023

•   Careful clinical examination of skin and mucous membranes, upper and lower respiratory tract and abdomen to exclude underlying infection, lymphadenopathy, and/or hepatosplenomegaly.

•   Clinicians should be aware that neutropenic patients might have only subtle symptoms of infection due to reduced inflammatory response.

•   In children and adults, clinical examination is crucial to detect congenital disorders. It should focus on growth, evidence of cognitive impairment, developmental delay, dysmorphism (mainly skeletal), nail, hair or skin abnormalities, signs of bronchiectasis due to recurrent chest infections, hepatomegaly or splenomegaly, organ malformation, evidence of superficial veins, and finally signs of photophobia, nystagmus, oculocutaneous albinism, and neuropathy. The absence of obvious clinical signs does not exclude the presence of a congenital disorder.

•   Cardiac function, presence of enlarged lymph nodes, joint symptoms, and symptoms compatible with autoimmune, metabolic, gastrointestinal, or nutritional diseases should also be considered.

GPS

A.4.Cc What is the diagnostic clinical criteria for children presenting with fever and neutropenia?

ASCO 2023

Febrile neutropenia (FN) is defined as an oral temperature of >38.3°C or two consecutive readings of >38.0°C for 2 h and an absolute neutrophil count (ANC) of <0.5 × 10⁹/l or expected to fall below 0.5 × 10⁹/l..

GPS

Laboratory work up for diagnosis

A.5.a. What is the approach to investigate children with neutropenia??

EHA-EuNet-INNOCHRON 2023

•  Patients with acute neutropenia, particularly in the presence of symptoms/signs of infection, may require immediate investigation and even hospitalization depending on the severity of neutropenia and symptoms.

•  For patients with chronic, isolated neutropenia without a phenotype suggestive of any underlying CN syndrome, a flowchart of basic investigation is recommended.

•  If the initial evaluation does not suggest ADAN, nor postinfectious or drug-induced neutropenia, the first level of investigation, possibly adjusted to the availability of the recommended tests

GPS

A.5.b. What are the first and second lines of investigations for children with neutropenia?

EHA-EuNet-INNOCHRON 2023

First-line investigations

•      Complete blood count (CBC)s, peripheral blood (PB) smear.

•      Biochemistry tests including liver and kidney function, c-reactive protein (CRP).

•      Vitamin B12 and folate.

•      Virology antibody screening (i.e., HepB, HepC, HIV, EBV, and CMV).

•      Thyroid hormones (FT3, FT4, TSH), antithyroid antibodies (anti-TG and anti-TPO).

•      Antineutrophil antibodies by granulocyte immunofluorescence test (GIFT) and/or granulocyte agglutination test (GAT).

•      Immunoglobulin levels and flow cytometric analysis of PB lymphocyte subsets,

•      Additional investigation in children: flow cytometric analysis of CD3+TCRα/β+CD4-CD8- (double negative) PB T lymphocytes.

Second-line investigations

•      CBCs in family members, serial blood counts twice a week over a period of 6 weeks to exclude CyN, copper; ceruloplasmin, anti-tissue transglutaminase IgA, deamidated gliadin peptide antibodies IgA/IgG and pancreatic isoamylase.

•      Additional investigation in children: rheumatoid factor (RF), antinuclear antibody (ANA), extractable nuclear antigen (ENA), and double stranded DNA (ds-DNA).

•      In children, young adults, and considered for adults: genetic investigations.

GPS

A.5.c How to confirm the diagnosis of congenital neutropenia?

EHA-EuNet-INNOCHRON 2023

•  Following negative results of first-level investigation, all patients with SCN and recurrent infections and/ or family history of severe neutropenia and typical anomalies should undergo genetic work-up using multigene next generation sequencing (NGS) methods.

•  Patients with congenital neutropenia may have positive anti-neutrophil antibodies. In case of severe infections patients should in spite positive antibodies undergo genetic testing

GPS

•  However, family history or clinical findings may suggest another specific neutropenia-associated gene to be sequenced. For example, in the presence of cardiomyopathy, TAZ (Barth syndrome) sequencing may be diagnostic, while in the presence of cardiac and genitourinary malformations sequencing of G6PC3 may lead to diagnosis. Poor growth, malabsorption, fatty stool, and bone malformation suggest SBDS mutations that are found in most patients with Shwachman-Diamond syndrome (SDS).

•  A targeted NGS panel including all genes known to be mutated in CN (>30) is a reasonable first step that provides uniform sequencing coverage for all genes of interest and requires simpler bioinformatics analysis.

•  The choice of genes within the panel should include not only all those that strictly cause neutropenia when mutated but also genes resulting in diseases in which neutropenia is a secondary feature (immunodeficiency/immune dysregulation, metabolic and nutritional deficiency, and other BMF syndromes) whole exome sequencing (WES) can also be used in cases where no mutations were detected in a panel

A.5.d. How to diagnose cyclic neutropenia?

EHA-EuNet-INNOCHRON 2023

Complete blood counts (CBC) in family members, serial blood counts twice or thrice a week over a period of 6 weeks to exclude CyN.

GPS

A.5.e. How to diagnose autoimmune neutropenia?

EHA-EuNet-INNOCHRON 2023

•   Antineutrophil antibody testing should be performed as first-line investigation in both children and adults.

•   Indirect granulocyte immunofluorescence test (GIFT) is recommended as a first-line assay in reference laboratories.

•   A positive GIFT in combination with laboratory tests and clinical picture can support diagnosis of autoimmune neutropenia (AIN) but does not exclude the diagnosis of other types of neutropenia.

•   With a negative indirect GIFT, if the clinical suspicion of AIN remains high, GIFT should be repeated several times.

GPS

A.5.f. Is family Screening indicated in patients with genetically proven congenital neutropenia?

EHA-EuNet-INNOCHRON 2023

•   Following identification of the responsible gene(s), Sanger sequencing is also recommended for mutation screening of the members of affected families.

•   Multigene NGS or WES ideally should include patient and parental DNA (trio analysis).

GPS

A.5.g. What is the role of bone marrow examination in the diagnosis of children with neutropenia?

EHA-EuNet-INNOCHRON 2023

Diagnostic BM with morphology, cytogenetics, and NGS of genes related to myeloid malignancies should be performed:

1.     In pediatric patients with severe and moderate chronic neutropenia with the exception of patients with primary AIN with positive anti-granulocyte antibodies and drug-induced neutropenia.

N.B: Patients with congenital neutropenia may have positive antibody test.

2.     In patients with suggested AIN but negative granulocyte antibody test, if patients suffer from recurrent infections.

3.     In any patients before G-CSF treatment.

Repeated BM follow-up should be performed in patients:

With decreasing ANC or additional changes in other blood cell counts (e.g., anemia and thrombocytopenia) or erythrocyte indices.

GPS

A.5.h. What is the role of flowcytometry for the diagnosis children presenting with chronic neutropenia?

EHA-EuNet-INNOCHRON 2023

FC is an important tool in the diagnosis of neutropenia associated with PID syndromes such as ALPS, CVID, and HIGM syndrome.

Assessment of a PNH clone by FC testing is also recommended.

Flow FISH is recommended when a telomere biology disorder is suspected.

GPS

A.5.i. What is the role of genetic testing in the diagnosis of children with neutropenia?

EHA-EuNet-INNOCHRON 2023

•   Genetic diagnosis is important to confirm the diagnosis of CN, estimate the risk for MDS/AML, support stem cell donor selection for patients, and family counseling.

GPS

•   When the clinical picture, inheritance, or bone marrow features (i.e., block at the promyelocyte stage) are indicative of a specific gene mutation, single-gene analysis by Sanger sequencing technique could be applied.

•   For CN where the clinical picture does not suggest a specific genetic cause, we recommend the use of NGS techniques such as multigene panels or targeted WES.

•   For patients for whom a genetic cause is not identified by the above methods, WGS and RNA-sequencing may be powerful diagnostic tools.

•   NGS analysis of bone marrow or peripheral blood for acquired somatic variants is recommended for patients with chronic neutropenia.

•   Screening for known mutations is recommended in family members.

•   It is important to validate germline mutations mainly in fibroblasts or hair follicles keratinocytes (cells from buccal swab are less indicated for possible blood contamination), in the presence of leukemic blasts in PB.

A.5.j. What is the required initial evaluation for children presenting with fever and neutropenia?

ASCO 2023

•   Adopt a validated risk stratification strategy and incorporate it into routine clinical management

Low

Strong

ASCO 2023

•   Obtain blood cultures at the onset of FN from all lumens of central venous catheters.

Low

Strong

ASCO 2023

•   Consider obtaining peripheral blood cultures concurrent with central venous catheter cultures.

Moderate

Conditional

ASCO 2023

•   Consider urinalysis and urine culture in patients where a clean-catch, mid-stream specimen is readily available

Low

Conditional

ASCO 2023

•   Obtain chest radiography only in patients with respiratory signs or symptoms.

Moderate

Strong

Table 4. Recommendations on treatment of neutropenia

B. Management of neutropenia in pediatric age groups

Source Guideline

Recommendations

QoE

SoR

B.1. What is the treatment of infection in patients with fever and non-severe neutropenia?

Fioredda et al 2011*

Individuals with an ANC >1.0 x 10*9 /L can be managed as per those with normal ANC..

GPS

B.2. What is the treatment of fever and neutropenia (FN)?

Infants with primary AIN should be excluded from these recommendations, since ANC is not indicative of infectious risk in these patients.

GPS

I. Initial treatment

In low-risk FN

ASCO 2023

·     Consider initial or step-down outpatient management if the infrastructure is in place to ensure careful monitoring and follow-up.

Moderate

Conditional

ASCO 2023

·     Consider oral antibacterial therapy administration if the patient is able to tolerate this route of administration reliably.

Moderate

Conditional

In high-risk FN

ASCO 2023

·     Use monotherapy with an antipseudomonal b-lactam, a fourth-generation cephalosporin or a carbapenem as empiric antibacterial therapy in pediatric high-risk FN

High

Strong

ASCO 2023

·     Reserve addition of a second anti-Gram-negative agent or a glycopeptide for patients who are clinically unstable, when a resistant infection is suspected, or for centers with a high rate of resistant pathogens

moderate

Strong

II. Ongoing management

Modification of treatment

ASCO 2023

·     In patients who are responding to initial empiric antibacterial therapy, discontinue double coverage for Gram-negative infection or empiric glycopeptide (if initiated) after 24-72 hours if there is no specific microbiologic indication to continue combination therapy.

Moderate

Strong

ASCO 2023

·     Do not broaden the initial empiric antibacterial regimen based solely on persistent fever in patients who are clinically stable.

Low

Strong

ASCO 2023

·     In patients with persistent fever who become clinically unstable, escalate the initial empiric antibacterial regimen to include coverage for resistant Gram-negative, Gram-positive and anaerobic bacteria.

Very low

Strong

Cessation of treatment

ASCO 2023

·     In both high-risk and low-risk FN patients who have been clinically well and afebrile for at least 24 hours, discontinue empiric antibacterial therapy if blood cultures remain negative at 48 hours if there is evidence of marrow recovery

Low

Strong

ASCO 2023

·     In patients with low-risk FN who have been clinically well and afebrile for at least 24 hours, consider discontinuation of empiric antibacterial therapy if blood cultures remain negative at 48 hours despite no evidence of marrow recovery.

Moderate

Conditional

B.3. What is the treatment of severe chronic neutropenia

I. The use of G-CSF

Fioredda et al 2011

·     Patients usually need life-time treatment.

GPS

·     The therapeutic target (ANC ≥1.0 × 10*9/L and ≤5.0 × 10*9/L) is considered achievable with a G-CSF starting dose of 5 μg/kg/d, but the individual variability of the response may require modifications of the subsequent doses.

GPS

·     It is suggested to increase G-CSF over 2 weeks up to doubling initial dose if ANC remain <1.0 × 10*9/L and to reduce G-CSF if ANC reach >5.0 × 10*9/L.

GPS

·     Maintain the initial dose if the target ANC (≥1.0 × 10*9/L and ≤5.0 × 10*9/L) is achieved and increase by 2.5 μg/kg/day every 5–7 days if ANC remains <1.0 × 10*9/L.

N.B: Depending on clinical situation and known underlying genotype doubling of G-CSF may be indicated up to 50µg/kg/day to evaluate G-CSF response

GPS

·     Experts agreed on the non-superiority of lenograstim vs. filgrastim as the number of infections was similar in patients treated with the two preparations.

GPS

·     The use of pegylated G-CSF in neutropenia has been rarely reported in pediatric age.

GPS

II. Hematopoietic stem cell transplantation (HSCT)

Fioredda et al 2025

Strong indications for HSCT include:

(1) Established transformation to MDS/Acute Leukemia or bone marrow dysplastic features with high‐risk acquired cytogenetic abnormalities (monosomy 7, trisomy 8, and trisomy 21) or with

a combination of acquired leukemia‐associated somatic mutations (e.g., RUNX1, ASXL1, and SETBP1). CSF3R mutations alone are not an indication of HSCT.

(2) CN due to mutations carrying an intrinsic high risk of leukemic

transformation per se, i.e., GATA2 mutations, high‐risk ELANE

mutations, or clones with biallelic TP53 mutations in SDS.

(3) No response to G‐CSF (doses > 20 mcg/kg/d to reach ANC of 1.0 × 109/L), poor response to G‐CSF (doses between 10 and 20 mcg/kg/d failing to reach ANC of 1.0 × 109/L) or poor control of infection irrespective of the G‐CSF dose.

Potential indications to HSCT

adequate management of infections with G‐CSF at “intermediate doses” (10–15 mcg/kg/d) with availability of a healthy HLA‐identical sibling or HLA identical matched donor.

Weak indication of HSCT

GCSF response at doses up to 10 μg/kg/d, good tolerability and compliance to daily subcutaneous injections, infections control, and unavailability of HLA matched donors.

GPS

GPS

B.4. What is the treatment of cyclic neutropenia (CyN)?

Fioredda et al 2011

·     In cyclic neutropenia (CyN) G-CSF treatment has been shown to shorten the degree and the duration of neutropenia conferring the patients a better quality of life. For these reasons, the long-term pattern of treatment was considered adequate to CyN.

GPS

Fioredda et al 2011

·     This has to be intended as a life-time treatment not to be performed daily but only during the lowest levels of neutrophils in cycling periods of neutropenia.

GPS

Fioredda et al 2011

·     Usually, patients affected by CyN need lower G-CSF doses (median 2.4 μg/kg/day) than SCN patients. A starting dose of 1–3 μg/kg/d should maintain ANC around 1.5 × 10*9/L; for lower counts the dosage may be increased up to two-fold within 2–4 weeks.

·     Given the ANC fluctuations it is suggested to calculate the final G-CSF dose after a number of observations.

GPS

Fioredda et al 2011

·     Daily administration during neutropenia is more appropriate than the intermittent schedule. Initial suggested dose during neutropenic periods is 2 μg/kg/day. If ANC target is not achieved, increases of 2 μg/kg/d every neutropenic phase are recommended

GPS

·     the panel recommends the use of G‐CSF in severe CN and in CyN, particularly in those patients with recurrent or severe infections.

·     The panel considers ANC over 1.0 × 109/L as the protective threshold against infections. For CyN, a lower nadir may be accepted.

·     In CyN, G‐CSF doses may be lower than in severe CN. The standard dose should be ≤3 mcg/kg/d continuously. G‐CSF may be also given every other day. Dosage may be adjusted to avoid nadir <0.5 × 109/L and clinical conditions such as mouth ulcers, fevers, or infections.

B.5. What is the treatment of idiopathic neutropenia (IN)?

Fioredda et al 2011

·     In the majority of cases, IN requires an on-demand treatment only during infections or surgery. In these patients an initial does of 1–2 μg/kg/d is considered sufficient to achieve goal ANC. 

GPS

Fioredda et al 2011

·     Some patients with a diagnosis of IN may have severe and/or recurrent infections and may require long-term treatment. A starting dose (1–2μg/kg/die) of G-CSF can be sufficient to achieve the goal ANC and a rhythm of 2–3 times/week may ensure protective values of neutrophils.

GPS

B.6. What is the treatment of autoimmune neutropenia (AIN)?

I. G-CSF

Fioredda et al 2011

·     The use of G-CSF in AIN is generally necessary only in case of severe infections and therefore the on-demand treatment is considered appropriate. Some forms of AIN may have severe and/or recurrent infections requiring a long-term treatment.

GPS

·     An initial low dose of G-CSF (1–2 mg/kg/die) to be subsequently adjusted.

GPS

II. Other treatment modalities:

Fioredda et al 2011

·     Various immune-regulating drugs (e.g., cyclosporine, methotrexate, low-dose cyclophosphamide) have been used in refractory cases, but overall efficacy has not been determined.

GPS

·     In case of an underlying immune dysregulation/deficiency, particularly in childhood, more targeted treatments (e.g., mycophenolate mofetil and rapamycin) may be used.

GPS

·     The role of rituximab (and other antibodies to CD20) is well established as effective treatment for many autoimmune disorders. However, its role as treatment for AIN is unclear.

GPS

Table 5. Prevention and monitoring of neutropenia

C. Prevention and monitoring of neutropenia in pediatric age groups

Source Guideline

Recommendations

QoE

SoR

I.    Prevention of complications

C.1. Identify groups at high-risk for infections)?

IDSA 2020

•   Pediatric patients actively receiving cytotoxic chemotherapy.

•   Down Syndrome.

•   Children with immune deficiency.

•   Patient with Central venous catheter.

•   Compromise of mucosal barriers (e.g. mucositis, typhlitis).

•   Myelosuppression.

•   Children with hematologic malignancies have an increased risk relative to children with solid tumors.

GPS

C.2. How to prevent infection; pharmacological (chemoprophylaxis) and non-pharmacological in high-risk population? 

1. Non-pharmacological

Martínez Campos et al 2023*

•   Personal protective equipment (gown, gloves. . .) in patients with contagious infection or colonization by multidrug resistant (MDR) microorganisms.

GPS

•   Aseptic technique in central venous catheter (CVC) handling.

GPS

•   Hand, surface and food preparation hygiene measures.

GPS

•   Chlorhexidine gluconate (CHG) baths (CHB) involve cleansing the patient’s body each day with CHG-impregnated wipes. Literature from pediatric patients with temporary CVCs inserted during critical care admissions suggests that CHB may have a role in reducing the rate of CLABSIs in these patients.

GPS

•   Avoid contact with pets associated with a high risk: turtles, cat’s litter, stables and new pets. This does not apply to other pets that are correctly vaccinated, in regard to which the sole precaution is to avoid contact with their faeces.

GPS

•   Prevention of IFI (high risk patients/situations)

-      Avoid flowers and plants in hospital rooms and the bedroom of the patient.

-      Hospital rooms with HEPA filters and positive pressure (>12 room air changes/h).

-      Use of FPP2 masks in closed spaces without HEPA filters (except the usual place of residence, where ventilation, avoiding plants, moisture and construction work).

-      Recommendation not supported by evidence:

§  Avoid pools, especially public or indoor ones.

§  Low bacteria diet not proven to reduce the incidence or severity of infection.

§  Personal protective equipment for patients in absence of microbial isolation that justifies it.

GPS

2.Pharmacological:

Martínez Campos et al 2023*

•   G-CSF in patients with solid tumors receiving intensive chemotherapy, who need to maintain cytotoxic dose/chemotherapy intensity and/or with previous history of fever neutropenia (FN).

GPS

•   Annual vaccination against seasonal flu of patients and their household contacts and health care workers.

GPS

C.3.a. What are the guidelines for Antibacterial Prophylaxis in different causes of neutropenia?

IDSA 2020

•        Consider systemic antibacterial prophylaxis administration in children with AML and relapsed ALL receiving intensive chemotherapy expected to result in severe neutropenia (absolute neutrophil count <500/µl for at least 7 days).

High

Conditional

IDSA 2020

•        Do not use systemic antibacterial prophylaxis routinely for children receiving induction chemotherapy for newly diagnosed ALL.

Low

Conditional

IDSA 2020

•        Do not use systemic antibacterial prophylaxis for children whose therapy is not expected to result in severe neutropenia (ANC <500/µl for at least 7 days).

Moderate

Strong

IDSA 2020

•        Do not use systemic antibacterial prophylaxis routinely for children undergoing autologous HSCT.

Moderate

Conditional

IDSA 2020

•        Do not use systemic antibacterial prophylaxis routinely for children undergoing allogeneic HSCT.

Moderate

Conditional

C.3.b. What to use (Type, dose, route)? how long?

IDSA 2020

•        Levofloxacin is the preferred agent if systemic antibacterial prophylaxis is planned.

Moderate

Strong

C.3.c. When should systemic antibacterial prophylaxis be stopped?

IDSA 2020

•        If systemic antibacterial prophylaxis is planned; we suggest that administration be restricted to the expected period of severe neutropenia (absolute neutrophil count <500/μL.

Low

Conditional

C.4.a. What are the guidelines for Antifungal Prophylaxis in different causes of neutropenia? When to start? & What to use (Type, dose, route)? & how long? How do we follow its side effects and effectiveness?

IDSA 2020

Acute myeloid leukemia (AML)

•        Administer systemic antifungal prophylaxis to children and adolescents receiving treatment of AML that is expected to result in profound and prolonged neutropenia.

High

Strong

Acute lymphoblastic leukemia (ALL)

IDSA 2020

•        Consider administering systemic antifungal prophylaxis to children and adolescents with newly diagnosed and relapsed ALL at high risk for invasive fungal disease (IFD)

Low

Conditional

•        Do not routinely administer systemic antifungal prophylaxis to children and adolescents with ALL at low risk for IFD.

Low

Strong

IDSA 2020

Other malignancies including most patients with lymphomas and solid tumors

•        Do not routinely administer systemic antifungal prophylaxis to children and adolescents with cancer at low risk for IFD, such as most pediatric patients with lymphomas and solid tumors.

Moderate

Strong

Hematopoietic stem cell transplantation (HSCT)

IDSA 2020

•        Administer systemic antifungal prophylaxis to children and adolescents undergoing allogeneic HSCT pre-engraftment and to those receiving systemic immunosuppression for the treatment of graft-versus host disease (GVHD).

Moderate

Strong

•        We suggest that systemic antifungal prophylaxis not be used routinely in children and adolescents undergoing autologous HSCT.

High

Strong

•        In choosing a mold-active agent, administer an echinocandin or a mold-active azole.

Moderate

Strong

•        Do not use amphotericin routinely as systemic antifungal prophylaxis.

Low

Strong

C.4.b. When should systemic antifungal prophylaxis be started and stopped?

IDSA 2020

If systemic antifungal prophylaxis is warranted, consider administration during periods of observed or expected severe neutropenia. For allogeneic HSCT recipients, consider administration during systemic immunosuppression for GVHD treatment

Low

Conditional

C.5. What are the guidelines for preventing Clostridium difficile infection (CDI) in children and adolescents with neutropenia? When to start? & What to use (Type, dose, route)? & what intervention? how long? How to follow the side effects and the effectiveness?

ASCO 2018

Do not use probiotics routinely for the prevention of CDI in children and adolescents with cancer and pediatric HSCT patients

Low

Conditional

ASCO 2018

Use either oral metronidazole or oral vancomycin for the treatment of non-severe CDI in children and adolescents with cancer and pediatric HSCT patients 

Low

Strong

ASCO 2018

Use oral vancomycin for the treatment of severe CDI in children and adolescents with cancer and pediatric HSCT patients

Low

Strong

ASCO 2018

Do not use monoclonal antibodies routinely for the treatment of CDI in children and adolescents with cancer and pediatric HSCT patients

Low

Strong

C.6. What are the guidelines for Prophylaxis against Pneumocystis jirovecii pneumonia (PJP)?

ASCO 2020

·     Risk for PJP pneumonia is highest in patients with leukemia and lymphoma, prophylaxis is also recommended for children with solid tumors undergoing chemotherapy that is likely to cause lymphopenia.

·     Data in patients with HIV shows that the risk of PJP is highest in those with CD4 counts under 200 x10*6/L, and one study from the solid organ transplantation population found that odds of PJP infection were significantly increased when absolute lymphocyte count (ALC) was < 500 x10*6/L.

·     Sulfamethoxazole (TMP-SMX) is highly effective.

·     For patients who do not tolerate TMP-SMX, pentamidine, dapsone, and atovaquone are alternative options,

·     Optimal duration of PJP prophylaxis is unknown. One guideline suggests continuing until 3 months after the end of therapy and normalization of lymphocyte count.

GPS

C.7. What are the guidelines for the prevention of oral and oropharyngeal Mucositis? When to start? & What to use (Type, dose, route)? & what intervention? how long? How to follow the side effects and the effectiveness?

Patel P et al, 2021

Use cryotherapy for older, cooperative pediatric patients receiving treatment for cancer or undergoing HSCT who will receive short infusions of melphalan or 5-fluorouracil.

GPS

Patel P et al, 2021

Consider using cryotherapy for older, cooperative pediatric patients receiving treatment for cancer or undergoing HSCT who will receive short infusions of chemotherapy associated with mucositis other than melphalan or 5-fluorouracil.

GPS

Patel P et al, 2021**

Do not administer palifermin routinely to pediatric patients with cancer receiving treatment for cancer or undergoing HSCT.

GPS

Patel P et al, 2021**

Use intraoral photo-biomodulation therapy in the red-light spectrum (620–750 nm) for pediatric patients undergoing autologous or allogeneic HSCT and for pediatric patients who will receive radiotherapy for head and neck carcinoma.

GPS

Patel P et al, 2021**

Consider using intraoral photo-biomodulation therapy in the red-light spectrum (620–750 nm) for pediatric patients who will receive radiotherapy for head and neck cancers other than carcinoma.

GPS

Patel P et al, 2021**

Do not administer GCSFs to pediatric patients receiving treatment for cancer or undergoing HSCT for the purpose of mucositis prevention.

GPS

C.8. What are the guidelines for growth factor therapy (granulocyte stimulating factor (GSF)?

Martínez Campos et al 2023

The use of G-CSF in in patients with solid tumors receiving intensive chemotherapy, who need to maintain cytotoxic dose/chemotherapy intensity and/or with previous history of FN reduces the duration of neutropenia.

GPS

C.9. How to provide vaccination? When to revaccinate? And how?

Martínez Campos et al 2023

Annual vaccination against seasonal flu of patients and their household contacts and health care workers.

Despite potential lack of efficacy in certain populations, the American Academy of Pediatrics and Center for Disease Control still recommend yearly influenza vacations in pediatric oncology patients based on potential benefit with low risk of reaction

GPS

II. Follow up and monitoring

C.10. What are the clinical indicators that should be assessed in each clinic visit?

EHA-EuNet 2023

•   Careful clinical examination of skin and mucous membranes, upper and lower respiratory tract and abdomen to exclude underlying infection, lymphadenopathy, and/or hepatosplenomegaly.

GPS

EHA-EuNet 2023

•   Vital signs: temperature, heart rate, respiratory rate, blood pressure and oxygen saturation.

•   Pediatric assessment triangle (early detection of sepsis).

•   Review of systems, including neurologic assessment, perfusion, skin and mucosae (oral and perianal, avoid rectal palpation), any area with pain, scars, devices.

GPS

C.11. What are the laboratory tests that should be done during the follow-up of the neutropenic child and how frequent?

EHA-EuNet 2023

In chronic neutropenia patients, we recommend performing CBC with differential WBC counts and morphological evaluation every 3–4 months.

GPS

EHA-EuNet 2023

When approaching adulthood, CN patients should be transferred to a dedicated hematology specialist.

GPS

C.12.a. How often the bone marrow study should be done?

EHA-EuNet 2023

·      Annual BM and cytogenetics follow-up should be performed in patients with

•        congenital BM failure syndromes independent of ANC and treatment with G-CSF. 

•        undefined SCN (after extensive investigation) with G-CSF treatment, may be considered.

GPS

EHA-EuNet 2023

·      Repeated BM follow-up should be performed in patients with decreasing ANC or additional changes in other blood cell counts (e.g., anemia and thrombocytopenia) or erythrocyte indices.

GPS

C.12.b. What are the surrogate markers of transformation into MDS/leukemia? What are the tests that should be done on the bone marrow sample?

EHA-EuNet 2023

·      The key markers of malignant transformation to MDS or leukemia in CN patients are the following: typical dysplastic features in PB (pseudo Pelger-Huet anomaly, hypogranulation, hyper segmentation, reticulated nucleus, and ringed-shaped nuclei) and BM (defective granulation, maturation arrest at myelocyte stage, and increase in monocytoid forms); cytogenetic abnormalities(e.g.,CSF3R, RUNX1, and ASXL1); and high frequency of somatic mutations in leukemia-associated driver genes.

·      The most common chromosomal defects in patients with CN at the MDS stage are trisomy 21 and monosomy 7.

GPS

GPS