endoscopic placement of the tube was performed without complications and initial tube feeding was introduced without problems. 5 days after PEG tube placement the patient developed fever and the PEG tube entry appeared red▶ Fig. 1a). Theredened and purulent (● fore, intravenous antibiotic treatment with metronidazol and ampicillin/sulbactam was started. The patient further developed diarrhea, which, in turn, caused a rash and eventually infection resulting in multiple deep cutaneous ▶ Fig. 1b). purulent perianal ulcers (● Examination of wound swabs led to detection of enterobacter cloacae. Due to a lack of improvement and persistent fever, antibiotic therapy was eventually escalated to piperacillin/tazobactam, teicoplanin and metronidazol. Total parenteral nutrition was initiated and tube feeding was paused. Yet, the lesion at the PEG tube entry did not heal adequately and fever remained. At this time WBC was 3 400/μl with an absolute neutrophil count (ANC) of 476/μl. GCSF (lenograstim; Granocyte®) treatment was introduced in a dose of 5 μg/kg body weight per day given as a continuous intravenous infusion to avoid further skin injury by subcutaneous injection. Over the following days, the gastrostomy wound began to heal nicely and the child ▶ Fig. 1c, d). The ANC became afebrile (● increased to a maximum of 1 794/μl.
Granulocyte Colony Stimulating Factor for Treatment of Neutropenia-associated Infection in Pearson Syndrome Granulozyten-Kolonie-stimulierender Faktor für die Behandlung Neutropenie-assoziierter Infektionen beim Pearson-Syndrom Introduction
▼
Pearson syndrome (PS; i. e. Pearson marrow–pancreas syndrome, OMIM #557000) is a rare mitochondrial disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, hepatic failure, renal tubulopathy and lactic acidemia. It is caused by sporadic deletions or duplications within the mitochondrial DNA (mtDNA). Its phenotype at onset is variable and may change with time as it depends on tissue distribution and relative amounts of abnormal mtDNA. Endoscopically placed gastrostomy (PEG) tubes are essential in some patients with PS for the treatment of failure to thrive in order to achieve normal growth and weight gain (Seneca S et al., Clin Genet 1997; 51: 338–342). We present the case of a 2-year-old girl, who suffered severe gastrostomy site infection during a period of neutropenia and was successfully treated with granulocyte colony stimulating factor (GCSF). We discuss the risks of PEG tube placement during neutropenia and the role of GCSF treatment in PS patients.
revealed an approximately 2.5 kb large mtDNA deletion without indication of duplication or deletion dimerization. In the following, the patient required regular packed red cell transfusions. Thrombocyte counts initially remained within a low to normal range (between 100 000/μl and 130 000/μl) and white blood cell counts (WBC) in the peripheral blood averaged 4 000/μl. No severe infections occurred. Growth and weight gain were normal within the first year of life following the 75th percentile but began to stagnate at the age of 16 months and eventually dropped below the 3rd percentile. Reduced stool levels of pancreatic elastase indicated exocrine pancreatic dysfunction. Thus, high caloric diet and pancreatin treatment were introduced. Due to refusal to eat, a nasogastric tube had to be placed and was not well tolerated over time. Therefore, a permanent PEG tube was required at the age of 2 ½ years. The a
b
c
d
Case report
▼
The patient is the first child of non-consanguineous parents of German origin. She was born full term after an uneventful pregnancy and developed well during the neonatal period. During a routine checkup at the age of 6 months, marked pallor was noted and hospital admission was initiated. At that time, the hemoglobin level had dropped to 2.9 g/dl. Due to the combination of refractory anemia, elevated lactate levels and the results of a bone marrow examination, which revealed vacuolization of erythroid and myeloid precursors as well as ringed sideroblasts, PS was suspected. After informed consent was obtained, the diagnosis was confirmed by PCR analysis of mtDNA, which
Fig. 1 a PEG wound infection during neutropenia in the reported child with Pearson syndrome. b Simultaneous development of multiple deep cutaneous purulent ulcers in the perianal region. Examination of wound swabs led to detection of enterobacter cloacae. c PEG site and d perianal region after 5 weeks of treatment with granulocyte colony stimulating factor (GCSF).
Baertling F et al. Granulocyte Colony Stimulating Factor … Klin Padiatr 2014; 226: 190–191 · DOI 10.1055/s-0034-1368760
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190 Short Communication
When GSCF treatment was finally discontinued, the ANC rapidly fell to 150/μl within 1 day and GCSF was reintroduced. It was eventually given subcutaneously at a dose of 10 μg per kg body weight per day. With daily GCSF treatment the ANC stabilized and no infections occurred within the following months.
Discussion
▼
The 2-year-old PS patient presented here recovered well when GCSF treatment was introduced in addition to antibiotic treatment during an episode of neutropenia and severe cutaneous infection following gastrostomy. Since PS is rare and patients often die within the first years of life, no controlled clinical trials evaluating therapeutic options for these patients have been conducted and no standardized guidelines for the management of this disease exist. Furthermore, detailed information on treatment of neutropenia in PS is scarce. In a few reports the application of GCSF in PS patients and its effectiveness in raising neutrophil counts has been mentioned without further discussion of dosage, mode of application or duration of treatment in more detail (Seneca S et al., Clin Genet 1997; 51: 338–342; Williams TB et al., Mol Genet Metab 2012; 106: 104– 107). In addition, there are no reports available on the potential effects of acute or preventive GCSF treatment of febrile neutropenic infection in PS. Generally, in acute febrile neutropenia, intravenous antibiotic treatment might be successful (James RM et al., Arch Dis Child 2006; 91: 852–858). However, in our patient, broad spectrum antibiotics alone did not bring about relevant improvement of the infectious complica-
tions. Healing of the gastrostomy wound occurred not before GCSF was started and the ANC rose significantly. 2 PS patients reported by Warris et al. died from invasive aspergillosis during a period of neutropenia despite adequate antifungal medication without GCSF being concomitantly administered (Warris A et al., Pediatr Infect Dis J 1999; 18: 739–741). GCSF has been shown to not only elevate the ANC but also to promote neutrophil function. Thus, it is likely that the additional effects of GCSF may have significantly contributed to improvement of the infection and wound healing in our case. The fact that gastrostomy was an elective procedure in our patient and low WBC had been previously noted raises the question of a possible use of GCSF treatment to prevent infectious complications. In general, the decision on treatment of afebrile neutropenia should depend on the clinical presentation and the relative risk of infection rather than the WBC or ANC alone (James RM et al., Arch Dis Child 2006; 91: 852–858). PEG tube placement has been shown to be an effective means of treating malnutrition in case of exocrine pancreas dysfunction in PS (Seneca S et al., Clin Genet 1997; 51: 338–342; van den Ouweland JM et al., Eur J Hum Genet 2000; 8: 195–203). Yet, to our knowledge, there is no clear information on WBC or ANC during the procedure and no reports on complications. Severe neutropenic infections can also occur after bone marrow transplantations (Babor F et al., Klin Padiatr 2012; 224: 160–165). A retrospective review conducted in patients who underwent this procedure suggested that elective PEG tube placement should be avoided in phases of acute neutropenia due to an increased risk of infection (Kaur S et al., J Pediatr Gastroenterol Nutr 2013; 56:
300–303). Yet, there are currently no data available on the use of preventive GCSF treatment in these patients or PS patients. In glycogen storage disease Ib (GSDIb), an inborn error of carbohydrate metabolism associated with neutropenia, PEG tube placement has been applied to meet the requirement of continuous or frequent carbohydrate administration more easily. Multiple reports (Schroten H et al., J Pediatr 1991; 119: 748–754; Steinmetz BA et al., J Pediatr Gastroenterol Nutr 2001; 33: 94–96) and our experience have shown that GSDIb patients tend to develop gastrostomy site complication. The case reported here demonstrates that there seems to be a risk for severe infection after gastrostomy in PS. Since PS patients are, furthermore, prone to infection due to malnutrition, GCSF treatment prior to PEG tube place should be considered in order to raise the ANC. We propose that in addition to antibiotics, GCSF should be kept in mind as important supportive measure for treating acute neutropenic infection in PS patients. Gastrostomy and other operative procedures should only be performed with high precaution in the presence of neutropenia. Furthermore, we suggest that preventive GSCF treatment should be considered before PEG tube placement in neutropenic PS patients in order to raise the ANC and to reduce the risk of infection.
Conflict of interest: The authors have no conflict of interest to disclose. F. Baertling, T. Meissner, A. Troeger, F. Pillekamp, E. Mayatepek, H.-J. Laws, F. Distelmaier (Duesseldorf, Germany)
Baertling F et al. Granulocyte Colony Stimulating Factor … Klin Padiatr 2014; 226: 190–191 · DOI 10.1055/s-0034-1368760
Downloaded by: NYU. Copyrighted material.
Short Communication 191
Granulocyte Colony Stimulating Factor for Treatment of Neutropenia-associated Infection in Pearson Syndrome Granulozyten-Kolonie-stimulierender Faktor für die Behandlung Neutropenie-assoziierter Infektionen beim Pearson-Syndrom Introduction
▼
Pearson syndrome (PS; i. e. Pearson marrow–pancreas syndrome, OMIM #557000) is a rare mitochondrial disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, hepatic failure, renal tubulopathy and lactic acidemia. It is caused by sporadic deletions or duplications within the mitochondrial DNA (mtDNA). Its phenotype at onset is variable and may change with time as it depends on tissue distribution and relative amounts of abnormal mtDNA. Endoscopically placed gastrostomy (PEG) tubes are essential in some patients with PS for the treatment of failure to thrive in order to achieve normal growth and weight gain (Seneca S et al., Clin Genet 1997; 51: 338–342). We present the case of a 2-year-old girl, who suffered severe gastrostomy site infection during a period of neutropenia and was successfully treated with granulocyte colony stimulating factor (GCSF). We discuss the risks of PEG tube placement during neutropenia and the role of GCSF treatment in PS patients.
revealed an approximately 2.5 kb large mtDNA deletion without indication of duplication or deletion dimerization. In the following, the patient required regular packed red cell transfusions. Thrombocyte counts initially remained within a low to normal range (between 100 000/μl and 130 000/μl) and white blood cell counts (WBC) in the peripheral blood averaged 4 000/μl. No severe infections occurred. Growth and weight gain were normal within the first year of life following the 75th percentile but began to stagnate at the age of 16 months and eventually dropped below the 3rd percentile. Reduced stool levels of pancreatic elastase indicated exocrine pancreatic dysfunction. Thus, high caloric diet and pancreatin treatment were introduced. Due to refusal to eat, a nasogastric tube had to be placed and was not well tolerated over time. Therefore, a permanent PEG tube was required at the age of 2 ½ years. The a
b
c
d
Case report
▼
The patient is the first child of non-consanguineous parents of German origin. She was born full term after an uneventful pregnancy and developed well during the neonatal period. During a routine checkup at the age of 6 months, marked pallor was noted and hospital admission was initiated. At that time, the hemoglobin level had dropped to 2.9 g/dl. Due to the combination of refractory anemia, elevated lactate levels and the results of a bone marrow examination, which revealed vacuolization of erythroid and myeloid precursors as well as ringed sideroblasts, PS was suspected. After informed consent was obtained, the diagnosis was confirmed by PCR analysis of mtDNA, which
Fig. 1 a PEG wound infection during neutropenia in the reported child with Pearson syndrome. b Simultaneous development of multiple deep cutaneous purulent ulcers in the perianal region. Examination of wound swabs led to detection of enterobacter cloacae. c PEG site and d perianal region after 5 weeks of treatment with granulocyte colony stimulating factor (GCSF).
Baertling F et al. Granulocyte Colony Stimulating Factor … Klin Padiatr 2014; 226: 190–191 · DOI 10.1055/s-0034-1368760
Downloaded by: NYU. Copyrighted material.
190 Short Communication
When GSCF treatment was finally discontinued, the ANC rapidly fell to 150/μl within 1 day and GCSF was reintroduced. It was eventually given subcutaneously at a dose of 10 μg per kg body weight per day. With daily GCSF treatment the ANC stabilized and no infections occurred within the following months.
Discussion
▼
The 2-year-old PS patient presented here recovered well when GCSF treatment was introduced in addition to antibiotic treatment during an episode of neutropenia and severe cutaneous infection following gastrostomy. Since PS is rare and patients often die within the first years of life, no controlled clinical trials evaluating therapeutic options for these patients have been conducted and no standardized guidelines for the management of this disease exist. Furthermore, detailed information on treatment of neutropenia in PS is scarce. In a few reports the application of GCSF in PS patients and its effectiveness in raising neutrophil counts has been mentioned without further discussion of dosage, mode of application or duration of treatment in more detail (Seneca S et al., Clin Genet 1997; 51: 338–342; Williams TB et al., Mol Genet Metab 2012; 106: 104– 107). In addition, there are no reports available on the potential effects of acute or preventive GCSF treatment of febrile neutropenic infection in PS. Generally, in acute febrile neutropenia, intravenous antibiotic treatment might be successful (James RM et al., Arch Dis Child 2006; 91: 852–858). However, in our patient, broad spectrum antibiotics alone did not bring about relevant improvement of the infectious complica-
tions. Healing of the gastrostomy wound occurred not before GCSF was started and the ANC rose significantly. 2 PS patients reported by Warris et al. died from invasive aspergillosis during a period of neutropenia despite adequate antifungal medication without GCSF being concomitantly administered (Warris A et al., Pediatr Infect Dis J 1999; 18: 739–741). GCSF has been shown to not only elevate the ANC but also to promote neutrophil function. Thus, it is likely that the additional effects of GCSF may have significantly contributed to improvement of the infection and wound healing in our case. The fact that gastrostomy was an elective procedure in our patient and low WBC had been previously noted raises the question of a possible use of GCSF treatment to prevent infectious complications. In general, the decision on treatment of afebrile neutropenia should depend on the clinical presentation and the relative risk of infection rather than the WBC or ANC alone (James RM et al., Arch Dis Child 2006; 91: 852–858). PEG tube placement has been shown to be an effective means of treating malnutrition in case of exocrine pancreas dysfunction in PS (Seneca S et al., Clin Genet 1997; 51: 338–342; van den Ouweland JM et al., Eur J Hum Genet 2000; 8: 195–203). Yet, to our knowledge, there is no clear information on WBC or ANC during the procedure and no reports on complications. Severe neutropenic infections can also occur after bone marrow transplantations (Babor F et al., Klin Padiatr 2012; 224: 160–165). A retrospective review conducted in patients who underwent this procedure suggested that elective PEG tube placement should be avoided in phases of acute neutropenia due to an increased risk of infection (Kaur S et al., J Pediatr Gastroenterol Nutr 2013; 56:
300–303). Yet, there are currently no data available on the use of preventive GCSF treatment in these patients or PS patients. In glycogen storage disease Ib (GSDIb), an inborn error of carbohydrate metabolism associated with neutropenia, PEG tube placement has been applied to meet the requirement of continuous or frequent carbohydrate administration more easily. Multiple reports (Schroten H et al., J Pediatr 1991; 119: 748–754; Steinmetz BA et al., J Pediatr Gastroenterol Nutr 2001; 33: 94–96) and our experience have shown that GSDIb patients tend to develop gastrostomy site complication. The case reported here demonstrates that there seems to be a risk for severe infection after gastrostomy in PS. Since PS patients are, furthermore, prone to infection due to malnutrition, GCSF treatment prior to PEG tube place should be considered in order to raise the ANC. We propose that in addition to antibiotics, GCSF should be kept in mind as important supportive measure for treating acute neutropenic infection in PS patients. Gastrostomy and other operative procedures should only be performed with high precaution in the presence of neutropenia. Furthermore, we suggest that preventive GSCF treatment should be considered before PEG tube placement in neutropenic PS patients in order to raise the ANC and to reduce the risk of infection.
Conflict of interest: The authors have no conflict of interest to disclose. F. Baertling, T. Meissner, A. Troeger, F. Pillekamp, E. Mayatepek, H.-J. Laws, F. Distelmaier (Duesseldorf, Germany)
Baertling F et al. Granulocyte Colony Stimulating Factor … Klin Padiatr 2014; 226: 190–191 · DOI 10.1055/s-0034-1368760
Downloaded by: NYU. Copyrighted material.
Short Communication 191
