Economic aspects of empiric antibiotic therapy for febrile neutropenia in children with cancer

Several antibiotic regimens have been proposed worldwide for empiric treatment of febrile neutropenia in children with cancer, but none of them shows clear advantages in terms of clinical efficacy. Therefore, other parameters, including drug acquisition costs, should be considered in the selection of treatment. Children receive a "fraction" of a standard daily dose, and this fraction is generally calculated on the basis of body weight; therefore, the cost of each day of therapy is determined by the packages available for each single drug. We calculated the acquisition costs of various drugs proposed for the empiric treatment of febrile neutropenia in children with cancer, and then we estimated the daily cost of therapy referred to different patient weights. In general, the combination regimen with ceftriaxone plus aminoglycoside turned out to be less expensive than other regimens (including monotherapy with third-generation cephalosporins or carbapenems).     

Analysis of 136 febrile neutropenic episodes in children with cancer: evaluation of treatment effectiveness and cost

In this study, 136 febrile neutropenic episodes were overviewed retrospectively. Factors affecting treatment success and cost were analyzed. Twenty percent of the episodes were microbiologically documented and 51% of the bacterial isolates were gram negatives. The most commonly used empirical therapies in febrile episodes were the combination of two drugs (58.0%), monotherapy (14.8%), and antibiotics plus fluconazole (20.6%). In lymphoproliferative tumors duration of fever and discharge from the hospital were longer. Administration of the hematopoietic growth factors shortened neither the duration of neutropenia nor fever and hospitalization. Treatment costs were higher in lymphoproliferative tumors, in bacteremia, and in episodes where glycopeptides, antifungal drugs, and hematopoietic growth factors were used. In conclusion, duration of neutropenia was a significant independent predictive factor for duration of fever. In the lymphoproliferative tumors, duration of fever was longer and cost of treatment was more than in the solid tumors.     

Severe Neutropenia in Japanese Patients with X-Linked Agammaglobulinemia

X-linked agammaglobulinemia (XLA) is clinically characterized by recurrent bacterial infections during early infancy. Although it is not a phagocytic disorder, XLA is sometimes associated with neutropenia. We conducted a nation-wide survey to determine the frequency of neutropenia among Japanese XLA patients. Responses were received from 87 (86%) of 101 patients in which BTK mutations were previously identified, and of these, 16 (18%) had neutropenia. All episodes of neutropenia occurred before initiation of intravenous immunoglobulin (IVIG) replacement therapy. Two XLA patients died of multiple organ failure caused by severe neutropenia and Pseudomonas sepsis before initiation of IVIG replacement therapy. These results suggest that, in some cases, severe bacterial infections in XLA patients might be caused not only by antibody deficiencies but also by neutropenia.     

Purine nucleoside phosphorylase deficiency: a new case report and identification of two novel mutations (Gly156A1a and Val217Ile), only one of which (Gly156A1a) is deleterious

Purine nucleoside phosphorylase (PNP) deficiency results in an autosomal recessive immunodeficiency disease characterized by initial involvement of cellular immunity and neurological manifestations with subsequent abnormalities of humoral immunity. The initial presentation and clinical course has varied widely in the relatively few published cases. The molecular basis has been reported in only 10 patients, precluding evaluation of phenotype-genotype relationships. We now report clinical, immunologic, and molecular findings in a new case of relatively early onset that emphasizes hypotonia and developmental delay as early manifestations. The patient carried two novel missense mutations (Gly56A1a and Val217Ile) on the same allele in apparent homozygosity. Expression of each of the mutant enzymes in vitro demonstrated that the Gly156A1a mutation abolished enzyme activity while the Val217Ile mutation was without obvious effect and is therefore a normal variant. Such "normal" polymorphisms might be associated with a variable response to the immunosuppressive PNP inhibitors currently in clinical trials.     

TCIRG1‐Associated Congenital Neutropenia

Severe congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30% of cases remains unknown. We report a five‐generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect cosegregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.     

Clinical characteristics and outcomes of clostridial bacteraemia in cancer patients

Clostridial bacteraemia is usually associated with substantial morbidity and mortality in cancer patients. However, clinical characteristics and risk factors for early mortality in this population are poorly described. We retrospectively studied cancer patients with clostridial bacteraemia treated between January 1996 and December 2011. We compared clinical manifestations between patients with solid tumour and haematological malignancy and assessed risk factors for 7-day mortality. In all, 164 cancer patients developed clostridial bacteraemia during the study period—85 (52%) with solid tumour and 79 (48%) with haematological malignancy. Common isolates were Clostridium perfringens (27%), Clostridium septicum (19%) and Clostridium tertium (14%). Solid tumour malignancy patients were more likely to have a focal gastrointestinal source for bacteraemia and were more likely to undergo subsequent surgery. Haematological malignancy patients were more often neutropenic and more often had no focal source of bacteraemia. Seven-day mortality was 20% (33/164) and did not vary based on malignancy type. The adjusted odds ratio of dying within 7 days of clostridial bacteraemia among patients with hypotension (40/164) was 7.2 (95% CI, 2.9–18.1) and in patients with acute haemolysis (7/164) was 10.5 (95% CI, 1.3–85.2). Clostridial species also impacted mortality; no patient with C. tertium bacteraemia died within 7 days. In conclusion, clinical manifestations of clostridial bacteraemia differed between patients with solid tumour and haematological malignancy, but 7-day mortality was similar. Patients with hypotension and haemolysis at time of bacteraemia were at increased risk for early death.     

Neutropenia and Primary Immunodeficiency Diseases

Primary immunodeficiency diseases (PID) are a heterogeneous group of congenital disorders of the immune system leading to recurrent infections, autoimmunity, malignancies, and hematological disorders. This review focuses specifically on inherited disorders associated with neutropenia, which may occur in isolation or as a feature of more complex immune disorders. It has been known for a long time that defined immunodeficiency syndromes, such as CD40L deficiency, WHIM syndrome, or Chédiak Higashi syndrome, may be associated with neutropenia even though the mechanisms are poorly understood. In some PID, neutropenia may result from chronic viral infection or from autoimmunity. Recently, the identification of several novel genetic defects (e.g., p14-deficiency, HAX1-deficiency, AK2-deficiency) has shed light on the pathophysiology of congenital neutropenia. This review summarizes the clinical, immunological, and genetic features of congenital neutropenia syndromes.     

Serum levels of mannose-binding lectin and the risk of fever in neutropenia pediatric cancer patients

BACKGROUND: Fever in neutropenia (FN) is a frequent complication in pediatric oncology. Deficiency of mannose-binding lectin (MBL), an important component of innate immunity, is common due to genetic polymorphisms, but its impact on infections in oncologic patients is controversial. This study investigated whether MBL serum levels at cancer diagnosis are associated with the development of FN in pediatric cancer patients. PROCEDURE: Serum MBL was measured using ELISA. Frequency, duration, and cause of FN were assessed retrospectively. Association with MBL level was analyzed using uni- and multivariate Poisson regression taking into account both intensity and duration of chemotherapy. RESULTS: In 94 children, with a cumulative follow-up time of 81.7 years, 177 FN episodes were recorded. Patients with both very low MBL levels (<100 microg/L; risk ratio (RR), 1.93; 95% CI, 1.14-3.28; P = 0.014) and normal MBL levels (>or=1,000 microg/L; RR, P = 0.011) had significantly more frequent FN episodes than patients with low MBL levels (100-999 microg/L). Patients with very low MBL levels had significantly more episodes of FN with severe bacterial infection (bacteremia or pneumonia; RR, 4.49; 1.69 = 11.8; P = 0.003), while those with normal MBL levels had more FN episodes with no microbial etiology identified (RR, 1.85; 1.14 = 3.03; P = 0.014). CONCLUSIONS: Very low MBL levels are associated with more frequent FN episodes, mainly due to severe bacterial infections. The surprising finding that children with normal MBL levels had more frequent FN episodes than those with low MBL levels needs testing in prospective studies.