Evaluation of children with non-chemotherapy-induced neutropenia and fever

INTRODUCTION — Children with fever and neutropenia should be evaluated promptly because fever may be the first manifestation of a life-threatening infection. The risk of infection in children with non-chemotherapy-induced neutropenia varies with the underlying cause of neutropenia (table 1).

The risk of infection in and evaluation of children with non-chemotherapy-induced neutropenia and fever will be discussed here. The conditions that cause neutropenia in children, the management of children with non-chemotherapy-induced neutropenia and fever, and the evaluation and management of children with chemotherapy-induced neutropenia and fever are discussed separately.

●(See "Overview of neutropenia in children and adolescents".)

●(See "Management of children with non-chemotherapy-induced neutropenia and fever".)

●(See "Fever in children with chemotherapy-induced neutropenia".)

DEFINITIONS

●Neutropenia – Neutropenia is generally defined as an absolute neutrophil count (ANC) <1500 cells/microL. (See "Overview of neutropenia in children and adolescents", section on 'Definitions and normal values'.)

The ANC is calculated using the following formula (calculator 1):

ANC = total white blood cell count (cells/microL) x (percent polymorphonuclear cells + percent bands) ÷ 100

The degree of neutropenia is classified as follows:

•Mild – ANC 1000 to 1500/microL

•Moderate – ANC 500 to 1000/microL

•Severe – ANC <500/microL

The effect of age and race and ethnicity on normal ANC values are discussed separately. (See "Overview of neutropenia in children and adolescents".)

●Fever – In neutropenic patients, fever is defined as a single oral temperature ≥38.3°C (101°F), a temperature ≥38°C (100.4°F) for longer than one hour, or two elevations >38°C (100.4°F) during a 12-hour period [1-3].

Rectal measurement of temperature should be avoided in neutropenic patients to avoid the possibility of introducing infection through mucosal trauma. Oral measurement is preferred to other nonrectal sites. An axillary temperature is acceptable if the patient is unable to use an oral thermometer. Noncontact temporal artery/forehead temperature measurements should not be used to make clinical decisions in neutropenic patients. (See "Fever in infants and children: Pathophysiology and management", section on 'Temperature measurement'.)

FEVER AND INFECTION IN CHILDREN WITH NEUTROPENIA

●Fever as a marker of infection – Fever is the most common and often the first clinical manifestation of serious infection in children with neutropenia. It may be the sole sign of occult infection. If a child with neutropenia develops fever, or if a previously healthy child is found to have isolated neutropenia during a febrile illness, the possibility of serious infection must be considered, particularly if the absolute neutrophil count is <1000 cells/microL (table 2).

Serious infection must also be considered in children with neutropenia who are afebrile and ill appearing (eg, hypothermic, hypotensive, listless, confused).

Patients with neutropenia who appear ill or are at increased risk of serious infection should receive empiric antibiotics after blood cultures are obtained. The management of infection in children with non-chemotherapy-induced neutropenia and fever is discussed separately. (See 'Routine cultures' below and "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'Risk-based management approach'.)

●Factors that affect susceptibility to infection – Factors that affect susceptibility to infection in children with neutropenia include (see "Overview of neutropenia in children and adolescents", section on 'Infection propensity'):

•The degree of neutropenia (table 2)

•Duration of neutropenia [4,5]

•Neutrophil function

•Ability of the bone marrow to respond to infection

•Function of other components of the immune system

•Integrity of the oral and gastrointestinal mucosa

•Presence of central venous catheters, other indwelling devices, or prosthetic implants (eg, Foley catheters, endotracheal tubes)

These clinical factors, largely determined by the underlying disorder, can be used to categorize the risk of infection in children with non-chemotherapy-induced neutropenia (table 1).

RISK CATEGORIZATION — The risk of infection in children with conditions associated with neutropenia that is not due to chemotherapy can be categorized according to the limited information about the frequency and severity of infections and the likelihood of marrow recovery. Factors that affect susceptibility to infection in children with neutropenia include the degree and duration of neutropenia, history and severity of previous infections, neutrophil function, and ability of the bone marrow to respond to an infectious insult and the function of other components of the immune system.

Low risk

Transient isolated neutropenia — Transient isolated neutropenia in children may occur during a febrile illness (typically viral) or as an adverse effect of certain medications (eg, antibiotics or anticonvulsants (table 3)) [4,6,7]. When due to a viral illness, neutropenia typically resolves within approximately three weeks. (See "Infectious causes of neutropenia", section on 'Common childhood viral infections' and "Drug-induced neutropenia and agranulocytosis".)

Children with transient isolated neutropenia are considered to be at low risk of serious infection (table 1). Limited evidence from observational studies suggests that when the child appears well, the absolute neutrophil count is ≥500 cells/microL, and the duration of neutropenia is <30 days, serious infection is uncommon [4,6,8-13]. In a retrospective study of 119 well-appearing children without underlying illness who were found to be neutropenic during a minor acute illness, infectious complications developed in 4 of 36 children who were neutropenic for >30 days (two developed stomatitis, one cellulitis, and one pneumonia) [4].

The evaluation and management of children with transient isolated neutropenia and fever are discussed separately. (See 'Evaluation' below and "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'Low risk'.)

Chronic autoimmune neutropenia — Chronic autoimmune neutropenia of childhood (also known as chronic idiopathic neutropenia and chronic benign neutropenia) typically occurs in children age 5 to 15 months [7,14,15]. Antineutrophil antibodies and spontaneous remission are characteristic. (See "Immune neutropenia", section on 'Autoimmune neutropenia'.)

Children with chronic autoimmune neutropenia are at low risk of serious bacterial infection (table 1) [7,14,16]. Most infections in children with chronic autoimmune neutropenia are viral infections and are unrelated to neutropenia.

The Italian Neutropenia Registry tracks episodes of meningitis, encephalitis, pneumonia, periodontitis, oral abscesses, deep abdominal infections, bacteremia, fungemia, cutaneous and subcutaneous abscesses, and otomastoiditis that are supported by clinical, imaging, biochemical, and/or microbiologic findings [16]. Among 61 children with autoimmune/idiopathic neutropenia included in the registry, the rate of infection was <1 per 1000 patient days at risk; 19 children had 39 infectious episodes (24 skin and soft tissue infections, 6 episodes of pneumonia; 3 bloodstream infections, 4 infections of the oral cavity, and 2 infections of the ear/nose/throat) [16].

Chronic autoimmune neutropenia also may occur in association with a variety of underlying diseases, including infections (eg, hepatitis B, primary abnormalities of B or T lymphocytes, autoimmune hemolytic anemia), especially if late in onset (after age 5 years) or prolonged in duration (longer than three years) [17]. (See "Immune neutropenia", section on 'Autoimmune neutropenia'.)

The evaluation and management of children with chronic autoimmune neutropenia/chronic idiopathic neutropenia are discussed separately. (See 'Evaluation' below and "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'Low-to-moderate risk'.)

Low-to-moderate risk — The risk of serious bacterial infection is low to moderate in well-appearing children with chronic autoimmune neutropenia, chronic idiopathic neutropenia, and cyclic neutropenia (table 1).

Cyclic neutropenia — Patients with cyclic neutropenia who are not treated with granulocyte colony-stimulating factor (G-CSF) experience bouts of severe neutropenia, which last for three to six days, at approximately 21-day intervals [18-20]. During these episodes, they often have fevers, oral ulcers, gingivitis, periodontitis, pharyngitis, adenopathy, and malaise (table 1). Meticulous oral hygiene is important in minimizing oral complications. More serious infections such as bacteremia, cellulitis, acute otitis media, sinusitis, pneumonia, or peritonitis occur less frequently [21]. Life-threatening illnesses, particularly necrotizing enterocolitis caused by Clostridium septicum [22,23], may occur, although they are uncommon. (See "Cyclic neutropenia", section on 'Clinical manifestations'.)

The prophylactic use of G-CSF reduces the risk and severity of infection [19]. (See "Cyclic neutropenia", section on 'G-CSF'.)

The evaluation and management of children with cyclic neutropenia are discussed separately. (See 'Evaluation' below and "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'Low-to-moderate risk'.)f

High risk

Ill appearance — Although fever is the most common and often the first sign of infection, serious infection must also be considered in children with neutropenia who are afebrile and ill appearing (eg, hypothermic, hypotensive, listless, confused).

The evaluation and management of ill-appearing children with non-chemotherapy-induced neutropenia are discussed separately. (See 'Evaluation' below and "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'High risk'.)

Severe congenital neutropenia — Severe congenital neutropenia presents shortly after birth with frequent and severe infections. Omphalitis, cellulitis, and perirectal abscesses are common during the first few months of life [24,25]. Disseminated infections, which may be life threatening, are frequently caused by Staphylococcus aureus, Escherichia coli, and Pseudomonas spp. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

Children with severe congenital neutropenia are at high risk of serious infection (table 1). Among 12 children with severe congenital neutropenia included in the Italian Neutropenia Registry between 2000 and 2009, there were a total of 69 infectious episodes (an average of 5.75 episodes per patient), approximately one-half of which required hospitalization [16]. Skin and soft tissue infections were most common (28 of 69), followed by pneumonia (13 of 69); ear, nose, or throat infection (9 of 69); and bloodstream infection (8 of 69).

Prophylactic use of G-CSF reduces, but does not eliminate, the risk and severity of infection. (See "Congenital neutropenia", section on 'Treatment'.)

Because of the risk of serious infection, patients with severe congenital neutropenia should be evaluated and treated aggressively when febrile. (See 'Evaluation' below and "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'High risk'.)

Aplastic anemia — Aplastic anemia is characterized by pancytopenia and hypocellular bone marrow due to injury to or loss of hematopoietic stem cells. Most cases of aplastic anemia in children are acquired and of unclear etiology. Inherited forms of aplastic anemia also occur (eg, Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis congenita). (See "Treatment of acquired aplastic anemia in children and adolescents" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

Children with aplastic anemia and fever are at high risk of serious infection (table 1). Invasive bacterial or fungal infection is a major cause of death in patients with severe aplastic anemia [26-28]. Neutropenia may last for months to years. (See "Treatment of acquired aplastic anemia in children and adolescents" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

Few studies describe infection in children with aplastic anemia and fever. In a sentinel review of 150 patients with aplastic anemia, clinical or microbiologically documented infection occurred in 69 percent of febrile episodes [29]. Infections of the respiratory tract were most common (32 percent), followed by the soft tissues (24 percent), blood (22 percent), gastrointestinal tract (17 percent), and urinary tract (6 percent).

In another retrospective multicenter review of 78 children diagnosed with aplastic anemia (6 with nonsevere aplastic anemia), 111 infectious episodes occurred in 42 children [27]. Bacteremia was the most commonly documented infection (23 episodes), followed by pneumonia (13 episodes), severe stomatitis (10 episodes), and 8 skin and soft tissue infections (including central venous catheter/tunnel infections). The distribution of the microbiologically documented isolates was as follows:

●Gram-positive – 18 episodes overall, 16 bacteremia episodes; gram-positive isolates included S. aureus, coagulase negative Staphylococcus, and streptococci

●Gram-negative – 12 episodes overall, 7 of the bacteremia episodes; gram-negative isolates included the Klebsiella spp, Enterobacter spp, Serratia spp, E. coli, and Pseudomonas spp

●Invasive fungal infections – 3 proven/probable and 2 possible infections of the respiratory tract

In a single-center review of 38 episodes of febrile neutropenia in 31 children from India with severe aplastic anemia, frequency and types of documented infectious episodes were similar [30].

Children with severe aplastic anemia and fever must receive urgent evaluation and empiric antimicrobial therapy. (See 'Evaluation' below and "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'High risk'.)

Neutropenia associated with primary immunodeficiency disorders — Neutropenia can occur in association with various other primary immunodeficiency disorders (eg, defects of cellular and humoral immunity, defects of phagocyte number or function, antibody deficiencies). The risk of infection in these disorders and the particular contribution of neutropenia to the risk of infection are not easily categorized given the multitude and variety of disorders. (See "Inborn errors of immunity (primary immunodeficiencies): Classification".)

General discussions of the risk, prevention, and management of infection in children with primary immunodeficiency disorders are provided in the topic reviews for specific types of disorders or specific disorders. For example:

●Disorders of phagocyte number and/or function (see "Primary disorders of phagocyte number and/or function: An overview")

●Combined immunodeficiencies (see "Combined immunodeficiencies: An overview")

●Wiskott-Aldrich syndrome (see "Wiskott-Aldrich syndrome")

●Agammaglobulinemia (see "Agammaglobulinemia")

Other conditions associated with neutropenia — Multiple other conditions are associated with isolated neutropenia or bone marrow failure. Some of these conditions are associated with a high risk of serious bacterial infection (eg, cartilage hair hypoplasia, reticular dysgenesis, and GATA2 deficiency).

EVALUATION — Children with fever and moderate-to-severe neutropenia should be evaluated promptly because they may be at risk for life-threatening infection. The risk and types of infection vary with the underlying cause of neutropenia (table 1).

In children at high risk of infection, the evaluation ideally should occur at a hospital with subspecialty services or at a facility that can arrange for transport to such a facility. Consultations with experts in hematology and/or infectious diseases may be necessary.

History and examination

●History – Important aspects of the history of a child with fever and neutropenia include [3]:

•New site-specific symptoms

•Antimicrobial prophylaxis (affects the choice of empiric antimicrobials)

•Infection exposures (eg, illness in family members or close contacts)

•History of documented infections or colonization

•Concomitant noninfectious cause of fever (eg, receipt of blood products)

•Underlying conditions that increase the risk of serious infection (eg, diabetes mellitus, recent surgery)

•Medication history (eg, glucocorticoids, which may mask fever; antibiotics and/or anticonvulsants, which can cause neutropenia (table 3))

•For patients who receive prophylactic granulocyte colony-stimulating factor – Adherence to the prescribed regimen and/or recent changes to the regimen

•Intravascular catheters or foreign body (increases the risk of infection)

•Immunization history (incomplete immunizations or uncertain immunization history may affect the choice of empiric antimicrobials)

●Physical examination – A complete physical examination should be performed and repeated periodically (at least once per day in hospitalized children). Signs of inflammation may become evident only when neutrophil counts are recovering.

The physical examination should focus on common sites of infection, including:

•Skin, especially folds, areas surrounding nail beds, and central venous catheter sites including the subcutaneous tunnel, if present

Mild erythema or tenderness should not be ignored; signs of inflammation in children with neutropenia may be subtle.

•Sinuses; sinus tenderness (rare in young children) should be evaluated

•Oropharynx, especially the gingival line and buccal mucosa (oral ulcers may indicate decreased marrow reserve)

•Lungs

•Abdomen

•Perineum, especially the perianal and labial regions

Routine cultures

●Blood cultures – A blood culture should be obtained in all children with fever and moderate-to-severe neutropenia. The culture should be obtained without delay in ill-appearing children and those at high risk of serious bacterial infection (table 1).

Anaerobic blood culture may be warranted in patients with abdominal signs and symptoms, particularly abdominal pain, and in patients with signs of buccal and perianal infections.

A blood culture should be obtained from each lumen of central catheter ports when such access is available. Although practices may vary from institution to institution, it is also acceptable practice to obtain peripheral blood cultures. Culturing blood from both peripheral and central sites helps to distinguish primary bacteremia from infection related to the catheter and to guide decisions about catheter removal [31]. Diagnosis of intravascular catheter-related infection is discussed separately. (See "Intravascular non-hemodialysis catheter-related infection: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Obtaining a second blood culture can help to differentiate true bacteremia from contamination. True bacteremia is more likely if the same commensal organism (eg, coagulase-negative Staphylococcus) is isolated from ≥2 blood cultures than from a single culture.

●Other cultures – Which other cultures are routinely obtained from children with fever and non-chemotherapy-induced neutropenia varies from institution to institution. Some experts routinely obtain urine cultures in females or young children who may not complain of urinary tract symptoms. We obtain urine cultures as clinically indicated. (See 'Additional studies as clinically indicated' below and "Urine collection techniques in infants and children with suspected urinary tract infection".)

Additional studies as clinically indicated — Additional studies should be obtained as clinically indicated. Examples include:

●Respiratory findings.

•Chest radiographs for children with signs or symptoms of lower respiratory tract infection [32].

A chest radiograph without infiltrates should be interpreted with caution since infiltrates may not appear until neutrophil counts are recovering. Patients with ongoing signs and symptoms may require further imaging with magnetic resonance imaging or computed tomography scanning.

•Rapid and sensitive respiratory diagnostic tests of nasopharyngeal secretions for viruses, as clinically appropriate. For example:

-Influenza (see "Seasonal influenza in children: Clinical features and diagnosis" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection")

-Respiratory syncytial virus (see "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children")

-Adenovirus (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection")

-Severe acute respiratory syndrome coronavirus 2 (see "COVID-19: Clinical manifestations and diagnosis in children", section on 'Approach to diagnosis')

●Gastrointestinal findings.

•Abdominal pain, particularly in children with cyclic neutropenia – Abdominal radiographs and/or ultrasonography (to evaluate Clostridium-associated necrotizing enterocolitis) [33].

•Diarrhea – Stool bacterial culture and/or polymerase chain reaction (PCR) testing panels, Clostridioides difficile toxin assay, and viral PCR testing panels and/or cultures. (See "Clostridioides difficile infection in children: Clinical features and diagnosis", section on 'Approach to diagnosis'.)

●Urinary symptoms, history of urinary tract infection (UTI), and/or urinary tract abnormalities – Urine culture if not obtained with routine cultures. (See "Urine collection techniques in infants and children with suspected urinary tract infection".)

Urinalysis should not be used to determine the need for urine culture. In a small observational study of children with UTI, pyuria was found in only 1 of 23 neutropenic patients, compared with 21 of 31 without neutropenia [34].

●Prolonged neutropenia, persistent diarrhea, or history of parasite exposure – Assay for ova and parasites.

●Altered mental status or meningeal signs – Lumbar puncture; platelet transfusion may be necessary before lumbar puncture in children who have thrombocytopenia as well as neutropenia. Antibiotic therapy should not be delayed in patients with concern for central nervous system infection but who cannot immediately undergo lumbar puncture. (See "Lumbar puncture in children", section on 'Contraindications'.)

●Abscess or sites with drainage – Gram stain and bacterial culture, fungal stain and culture, acid-fast bacilli stain and culture, and possibly fluorescent antibody stains or PCR tests.

Laboratory tests not routinely recommended

●Serum galactomannan antigen detection – Serum galactomannan antigen detection is not routinely recommended in the initial evaluation of children with non-chemotherapy-induced neutropenia and fever because of its poor positive predictive value and inability to exclude non-Aspergillus molds [35,36].

●Next-generation sequencing – Although data are emerging regarding the utility of next-generation sequencing of microbial cell-free deoxyribonucleic acid (DNA) testing in patients with febrile neutropenia, such testing is not routinely recommended [37].

SUMMARY AND RECOMMENDATIONS

●Definitions – Neutropenia is generally defined as an absolute neutrophil count (ANC) <1500 cells/microL (calculator 1). In neutropenic patients, fever is defined as a single oral temperature ≥38.3°C (101°F), a temperature ≥38°C (100.4°F) for longer than one hour, or two elevations >38°C (100.4°F) during a 12-hour period. (See 'Definitions' above.)

●Infection in children with neutropenia – Although fever is the most common and often the first clinical manifestation of serious infection in children with neutropenia, serious infection can occur in the absence of fever. Factors that affect susceptibility to infection in children with neutropenia include the degree and duration of neutropenia, neutrophil function, the ability of the bone marrow to respond to an infectious insult, and the function of the other components of the immune system. (See 'Fever and infection in children with neutropenia' above.)

●Risk categorization – The risk and types of infection in children with non-chemotherapy-induced neutropenia vary with the underlying disorder (table 1).

•Low risk – Transient isolated neutropenia in children may be related to a febrile illness (typically viral) or certain medications (table 3). The risk of serious infection in children with transient neutropenia is low, particularly when the child appears well, the ANC is ≥500 cells/microL, and the duration of neutropenia is <30 days. (See 'Transient isolated neutropenia' above.)

Children with chronic autoimmune neutropenia (also known as chronic idiopathic neutropenia and chronic benign neutropenia) have a low risk of infection. They typically present with mild infections (eg, upper respiratory tract infection, otitis media, skin infection) but may (very rarely) develop serious bacterial infections (eg, pneumonia, meningitis, sepsis). (See 'Chronic autoimmune neutropenia' above.)

•Low-to-moderate risk – Children with cyclic neutropenia have a low-to-moderate risk of infection. During episodes of neutropenia they often have fevers, oral ulcers, gingivitis, periodontitis, lymphadenopathy, and malaise. More serious infections (eg, bacteremia, cellulitis, acute otitis media, pneumonia, peritonitis) occur less frequently. Life-threatening illnesses (eg, Clostridium septicum necrotizing enterocolitis) are uncommon. Uncharacteristic fever patterns, atypical oral lesions, and localized findings, particularly abdominal pain, during the neutrophil nadir should increase suspicion for more serious infection. (See 'Cyclic neutropenia' above.)

•High risk – Ill-appearing children, children with severe congenital neutropenia, children with acquired or inherited aplastic anemia, and children with other conditions associated with neutropenia (eg, bone marrow failure and immunodeficiency syndromes) are at high risk for infection. The types of infection vary with the underlying disorder (table 1). (See 'High risk' above.)

●Evaluation – Children with non-chemotherapy-induced neutropenia and fever should be evaluated promptly because fever may be the first manifestation of a life-threatening infection. The risk and types of infection vary with the underlying cause of neutropenia (table 1). Repeated examination of the most common sites of infection (eg, skin, sinuses, oropharynx, lungs, abdomen, and perineum) is essential. (See 'History and examination' above.)

We routinely obtain blood cultures in children with non-chemotherapy-induced neutropenia and fever. For children with central catheters, we obtain blood cultures from each lumen and peripheral blood cultures. We obtain additional studies (eg, chest radiograph, viral studies, urine cultures) as clinically indicated. (See 'Routine cultures' above and 'Additional studies as clinically indicated' above.)

●Management – The management of children with non-chemotherapy-induced neutropenia and fever is discussed separately. (See "Management of children with non-chemotherapy-induced neutropenia and fever".)