Chronic neutropenia: how best to assess severity and approach management?

INTRODUCTION: Neutropenia is a relatively common finding in medical practice and the medical approach requires a gradual and pertinent diagnostic procedure as well as adapted management. AREAS COVERED: The area of chronic neutropenia remains fragmented between diverse diseases or situations. Here physicians involved in different aspects of chronic neutropenia gather both the data from medical literature till the end of May 2021 and their experience to offer a global approach for the diagnosis of chronic neutropenia as well as their medical care. EXPERT OPINION: In most cases, the neutropenia is transient, frequently related to a viral infection, and not harmful. However, neutropenia can be chronic (i.e. >3 months) and related to a number of etiologies, some clinically benign, such as so-called 'ethnic' neutropenia. Autoimmune neutropenia is the common form in young children, whereas idiopathic/immune neutropenia is a frequent etiology in young females. Inherited neutropenia (or congenital neutropenia) is exceptional, with approximately 30 new cases per 106 births and 30 known subtypes. Such patients have a high risk of invasive bacterial infections, and oral infections. Supportive therapy, which is primarily based on daily administration of an antibiotic prophylaxis and/or treatment with granulocyte-colony stimulating factor (G-CSF), contributes to avoiding recurrent infections.

Late-onset and long-lasting autoimmune neutropenia: an analysis from the Italian Neutropenia Registry.

Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.

Resistance to Antibiotics of Uropathogen Bacteria Isolated From Urine and Blood in Pediatric Cancer Patients: A Single Center, 12-year Study.

Resistant pathogens have become a major healthcare problem in children with cancer, causing different kinds of infections such as the bloodstream ones, most common, and most frequently described and the urinary tract ones, of which less data are available. We analyzed and compared the proportions, and the trends of resistance in pathogens isolated from blood and urines in children with cancer followed in IRCCS Istituto Giannina Gaslini, Genova, Italy, from January 2007 to December 2018. Overall, 345 strains detected in urines and 282 in bloodstream infections were analyzed. Enterobacteriales were the most frequently isolated pathogens. During the study period in urines, there was a significant increase of resistance to ceftazidime, ciprofloxacin, piperacillin/tazobactam, and trimethoprim-sulfamethoxazole, but pathogens from blood were significantly more frequently resistant to amikacin, piperacillin/tazobactam, and combination therapy piperacillin/tazobactam+amikacin, even if with a decreasing trend during the study period. These data confirm the importance of surveillance of isolated microorganism and antibiotic resistance in cancer children.

HSCT may lower leukemia risk in ELANE neutropenia: a before-after study from the French Severe Congenital Neutropenia Registry.

ELANE neutropenia is associated with myelodysplasia and acute leukemia (MDS-AL), and severe infections. Because the MDS-AL risk has also been shown to be associated with exposure to GCSF, since 2005, in France, patients receiving high daily GCSF doses (>15 µg/kg/day) are eligible for HSCT, in addition to classic indications (MDS-AL or GCSF refractoriness). We analyzed the effect of this policy. Among 144 prospectively followed ELANE-neutropenia patients enrolled in the French Severe Congenital Neutropenia Registry, we defined two groups according to period: "before 2005" for those born before 2005 and followed until 31/12/2004 (1588 person-years); and "after 2005" comprised of those born after 2005 or born before 2005 but followed after 2005 until 31/03/2019 (1327 person-years). Sixteen of our cohort patients underwent HSCT (14 long-term survivors) and six developed MDS-ALs. Six leukemic transformations occurred in the before-2005 group and none after 2005 (respective frequencies 3.8 × 10-3 vs. 0; P < 0.01), while four HSCTs were done before 2005 and 12 since 2005 (respective HSCT rates increased 2.5 × 10-3 vs. 9 × 10-3; P < 0.01). Our results support early HSCT for patients with ELANE mutations who received high GCSF doses, as it might lower the risk of leukemic transformation.

Definition of Opportunistic Infections in Immunocompromised Children on the Basis of Etiologies and Clinical Features: A Summary for Practical Purposes.

Opportunistic Infections (OIs) still remain a major cause of morbidity and death in children with either malignant or nonmalignant disease. OIs are defined as those infections occurring due to bacteria, fungi, viruses or commensal organisms that normally inhabit the human body and do not cause a disease in healthy people, but become pathogenic when the body's defense system is impaired. OIs can also be represented by unusually severe infections caused by common pathogens. An OI could present itself at the onset of a primary immunodeficiency syndrome as a life-threatening event. More often, OI is a therapyassociated complication in patients needing immunosuppressive treatment, among long-term hospitalised patients or in children who undergo bone marrow or solid organ transplantation. The aim of the present review is to provide a comprehensive and 'easy to read' text that briefly summarises the currently available knowledge about OIs in order to define when an infection should be considered as opportunistic in pediatrics as a result of an underlying congenital or acquired immune-deficit.

Magnusiomyces clavatus infection in a child after allogeneic hematotopoetic stem cell transplantation: Diagnostic and therapeutic implications.

Magnusiomyces clavatus is an ascomycetous fungus causing invasive disease in immuno-compromised patients. Neutropenia, contaminated venous catheters, previous antifungal treatment are risk factors for this infection. We report a case of Magnusiomyces clavatus fungemia with pulmonary, renal and skin localizations in a 6-year-old boy with prolonged neutropenia because of three allogeneic hematopoietic stem cell transplantations. The infection was controlled by aggressive and strictly monitored combination therapy with voriconazole and liposomial-ampthotericine-B along with durable recover from neutropenia.