Roberta Ghilardi

Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica).

Congenital and acquired neutropenia are rare disorders whose frequency in pediatric age may be underestimated due to remarkable differences in definition or misdiagnosed because of the lack of common practice guidelines. Neutropenia Committee of the Marrow Failure Syndrome Group (MFSG) of the AIEOP (Associazione Italiana Emato‐Oncologia Pediatrica) elaborated this document following design and methodology formerly approved by the AIEOP board. The panel of experts reviewed the literature on the topic and participated in a conference producing a document which includes a classification of neutropenia and a comprehensive guideline on diagnosis of neutropenia. Pediatr Blood Cancer 2011;57:10–17.

Congenital and acquired neutropenias consensus guidelines on therapy and follow‐up in childhood from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato‐Oncologia Pediatrica)

The management of congenital and acquired neutropenias presents some differences according to the type of the disease. Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is not standardized and scanty data are available on the best schedule to apply. The frequency and the type of longitudinal controls in patients affected with neutropenias are not usually discussed in the literature. The Neutropenia Committee of the Marrow Failure Syndrome Group (MFSG) of the Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP) elaborated this document following design and methodology formerly approved by the AIEOP board. The panel of experts reviewed the literature on the topic and participated in a conference producing a document that includes recommendations on neutropenia treatment and timing of follow-up.

Infectious complications in children with severe congenital, autoimmune or idiopathic neutropenia: a retrospective study from the Italian Neutropenia Registry.

We describe the incidence and characteristics of infections in children with severe congenital neutropenia (SCN), autoimmune neutropenia (AN) and idiopathic neutropenia (IN). Data extracted from the Italian Neutropenia Registry on 73 patients with 108 episodes of infections were collected from 2000 to 2009. All SCN patients with SCN and one third of AN and IN experienced at least 1 infectious episode, equating to 5.7 infections/patient in SCN and approximately 0.6 in AN and IN. The rate of infections before diagnosis of neutropenia was 6.35/1000 patient-days at risk in SCN, 0.48 in AN and 0.71 in IN (P < 0.001) and significantly decreased after diagnosis. Skin and subcutaneous abscesses and cellulitis were the most frequent types of infection encountered, followed by pneumonia. Infections are an important clinical issue in the management of neutropenic patients, even in those considered at lower risk.

Autoimmune neutropenia of infancy: Data from the Italian neutropenia registry

ing these with HFE genetic profiles. The local Ethics Committee approved the protocol. We analyzed data from all the 159 patients admitted in the study period with suspected iron overload based on high TS (above 55% in men and 45% in women) and/or SF (> 322 ng/mL), who had undergone MRI-T2* for heart, liver, spleen, and/or pancreas iron overload and had been screened for the presence of HFE mutations by allele-specific PCR (polymerase chain reaction). The calculations of liver iron concentration (LIC) values were based on liver MRI-T2* measurements, using the Thalassemia-Tools software (Cardiovascular Imaging Solutions, London, UK). Mutations in the HFE gene were identified in 109/159 (68.6%) patients. The most common mutation in our sample was H63D, present in 91 patients (57.2%): 14 (8.8%) were homozygous, 69 (43.4%) heterozygous, and 8 (5%) compound heterozygous for C282Y/H63D. For the C282Y mutation, in contrast, only 5 patients (3.1%) were homozygous and 11 (6.9%) were heterozygous. The S65C mutation was detected in heterozygous state in 2 (2.5%) cases. All 159 patients underwent abdominal MRI-T2* and 126 underwent cardiac MRI-T2* too. Only 3 out of 126 cardiac MRIs had a positive T2* result, mild cardiac overload (T2*: 18.98, 19.14, and 19.8 ms). Of these, two patients had the H63D mutation (1 homozygous and 1 heterozygous) and one patient did not have any of the mutations studied. In the liver, 61 (38.4%) patients had iron overload (T2*:< 11.4 ms and LIC> 2.0 mg/g) of which 57 (35.8%) were light (T2*: 3.83–11.4 ms and LIC: 2.01– 6.86 mg/g), and four (2.5%) moderate (T2*: 2.0–3.8 ms and LIC: 7.06–13.56 mg/g). Of these patients with liver overload, 27.9% were C282Y carriers (8.2% homozygous, 11.5% heterozygous, and 8.2% compound heterozygous C282Y/H63D), and 50.8% carried the H63D mutation (14.8% in homozygosis and 36.1% in heterozygosis). Only 12 (19.7%) patients with liver overload did not have the HFE mutation. The presence of C282Y mutation (in either homo or heterozygosis), compound heterozygous (C282/H63D), and H63D in homozygosis was significantly associated with a higher frequency of iron overload in the liver as measured by T2* (P5 0.001). However, this was not true in patients with H63D in heterozygosis or absence of mutation (P5 0.42), in which overload frequency was 68.4% and 29.1%, respectively. Pancreatic overload was diagnosed in 33 patients (21%), and 56 patients (35.7%) had splenic overload (Table I). The presence of the C282Y was associated with an overall higher frequency of iron overload. There was also a relatively high frequency (37.3%) of abnormal T2* values in H63D mutants both in the liver and in the spleen, and the frequency of splenic iron overload in H63D mutants was similar to that associated with the C282Y mutation. SF results were available for 152 patients. Median SF was 647 ng/mL (72–13,625), and in 138 patients (90.8%) SF was abnormally high. Overall, in 28 patients (18.2%) serum levels were higher than 1,000 ng/mL, in 80 patients (54%) they varied from 501 to 1,000 ng/mL and in 30 (20.3%) they ranged from 324 to 500 ng/mL. Serum TS was obtained from 94 patients, with a median of 42% (31–57) and elevated results in 32 (34%) of the tests. Considering MRI findings as standard, SF was the most sensitive test (sensitivity 94.7%, specificity 11.8%), whereas TS was the most specific (sensitivity 34%, specificity 65.4%), indicating that they might be complementary. Sensitivity and specificity values were similar in patients with and without HFE mutation. Iron overload prevalence was different according to the affected organ or the type of HFE mutation; over 50% of patients with liver iron overload carried the H63D mutation, and two out of three patients who had cardiac iron overload were also H63D carriers. A total of 38% of the H63D carriers presented with iron overload in the liver and spleen and 22% in the pancreas, showing that this mutation alone might correlate with iron overload. It is worth noticing, however, that the absence of HFE mutations does not rule out the presence of other mutations associated with hereditary hemochromatosis. Our study demonstrates, in a large sample of Brazilian patients, that MRI-T2* is a non-invasive, accurate, and sensitive technique for the detection of low levels of iron overload in patients with HH type 1. Excessive iron stores in the liver were detected in 39% of patients, showing that iron accumulation begins in the liver [6]. Given the observation that MRI is an accurate and safe tool to measure iron stores in these organs, we believe that this technology should be incorporated in the investigation of suspected cases of hemochromatosis and contribute to guide therapeutic decisions such as phlebotomy.

Diagnostic value of cell bound and circulating neutrophil antibody detection in pediatric neutropenia

Chronic benign neutropenia of infancy includes primary autoimmune neutropenia (pAIN) and chronic idiopathic neutropenia (CIN). A diagnosis of CIN is supported by the absence of free and/or cell‐bound neutrophil autoantibodies, which can be detected by flow cytometry with the indirect‐granulocyte immunofluorescence test (I‐GIFT) and direct‐granulocyte immunofluorescence test (D‐GIFT), respectively. Conclusive evidence is lacking on the diagnostic value of the D‐GIFT, whose performance requires specific laboratory expertise, may be logistically difficult, and hampered by very low neutrophil count in patient samples. This study investigated whether the evaluation of D‐GIFT improves the diagnostic accuracy of pediatric neutropenia.

Autoimmune neutropenia of childhood secondary to other autoimmune disorders: Data from the Italian neutropenia registry

To the Editor: As a sequel to our previous study, we would like to further comment on the topic of desiderosmia (olfactory cravings). We previously described three patients with iron deficiency anemia (IDA) presenting with symptoms of olfactory cravings, with compulsion to smell a variety of substances. We have designated the name, “desiderosmia,” for this novel symptom. After treatment for IDA, the patients’ olfactory craving symptoms resolved. In this article, we reviewed English medical literature and the World Wide Web to determine if such olfactory cravings associated with iron deficiency anemia had been previously reported. We searched the PubMed, Google, and Google Scholar to find publications, reports, presentations, or testimonies of individuals in online blogs using a combination of search terms including “nasal,” “olfactory,” “smell,” “craving,” “iron deficiency,” and “anemia.” Although this specific symptom has only been previously published once in medical literature, we did find a large number of online patients self-reporting such a phenomenon potentially corroborating our practice experience. Upon further exploration using Google search engine, we came across a number of online blog posts, mostly in pregnancy blogs, in which participants described this unique symptom. These women reported powerful cravings of olfaction, and were frequently overtaken by a strong desire to smell certain odors. The types of substances craved and their associated medical conditions (when reported) are summarized in Supporting Information Table S1. The effects of IDA on the olfactory system have only been minimally explored. It is known that several key enzymes necessary for proper olfaction such as neuronal nitric oxide synthase, tryptophan dioxygenase, and tyrosine hydrolase require either heme or inorganic iron for structure or activity. In an animal study, iron-deficient rats were observed to have prolonged exploratory time (sniffing) for attractive odorants compared to controls. The hypothesis was that IDA decreased the activity of these enzymes resulting in a net reduction of inhibitory olfactory inputs. Another study compared the olfactory function of IDA patients with healthy subjects and found a heightened sensitivity (lower threshold) in detecting odorant among patients with IDA. These reports support a plausible association between the physiological changes in olfaction and iron store. The mystery behind the pathophysiology of this symptom is a driving factor for further research and exploration. Additionally, it would be interesting to investigate what factors potentially account for the discrepancy between the volume of reports seen in online blogs and those documented in clinical practice. Perhaps these symptoms are being overlooked or not screened for in clinical encounters, and therefore leading to a misunderstanding of this symptom in practice. By placing a name to this symptom, we hope to contribute to a better understanding and recognition of these olfactory cravings by both patients and physicians.

Autoimmune neutropenia of childhood secondary to other autoimmune disorders

To the Editor: As a sequel to our previous study, we would like to further comment on the topic of desiderosmia (olfactory cravings). We previously described three patients with iron deficiency anemia (IDA) presenting with symptoms of olfactory cravings, with compulsion to smell a variety of substances. We have designated the name, “desiderosmia,” for this novel symptom. After treatment for IDA, the patients’ olfactory craving symptoms resolved. In this article, we reviewed English medical literature and the World Wide Web to determine if such olfactory cravings associated with iron deficiency anemia had been previously reported. We searched the PubMed, Google, and Google Scholar to find publications, reports, presentations, or testimonies of individuals in online blogs using a combination of search terms including “nasal,” “olfactory,” “smell,” “craving,” “iron deficiency,” and “anemia.” Although this specific symptom has only been previously published once in medical literature, we did find a large number of online patients self-reporting such a phenomenon potentially corroborating our practice experience. Upon further exploration using Google search engine, we came across a number of online blog posts, mostly in pregnancy blogs, in which participants described this unique symptom. These women reported powerful cravings of olfaction, and were frequently overtaken by a strong desire to smell certain odors. The types of substances craved and their associated medical conditions (when reported) are summarized in Supporting Information Table S1. The effects of IDA on the olfactory system have only been minimally explored. It is known that several key enzymes necessary for proper olfaction such as neuronal nitric oxide synthase, tryptophan dioxygenase, and tyrosine hydrolase require either heme or inorganic iron for structure or activity. In an animal study, iron-deficient rats were observed to have prolonged exploratory time (sniffing) for attractive odorants compared to controls. The hypothesis was that IDA decreased the activity of these enzymes resulting in a net reduction of inhibitory olfactory inputs. Another study compared the olfactory function of IDA patients with healthy subjects and found a heightened sensitivity (lower threshold) in detecting odorant among patients with IDA. These reports support a plausible association between the physiological changes in olfaction and iron store. The mystery behind the pathophysiology of this symptom is a driving factor for further research and exploration. Additionally, it would be interesting to investigate what factors potentially account for the discrepancy between the volume of reports seen in online blogs and those documented in clinical practice. Perhaps these symptoms are being overlooked or not screened for in clinical encounters, and therefore leading to a misunderstanding of this symptom in practice. By placing a name to this symptom, we hope to contribute to a better understanding and recognition of these olfactory cravings by both patients and physicians.

Autoimmune neutropenia of childhood secondary to other autoimmune disorders: Data from the Italian neutropenia registry: FARRUGGIA et al.

To the Editor: As a sequel to our previous study, we would like to further comment on the topic of desiderosmia (olfactory cravings). We previously described three patients with iron deficiency anemia (IDA) presenting with symptoms of olfactory cravings, with compulsion to smell a variety of substances. We have designated the name, “desiderosmia,” for this novel symptom. After treatment for IDA, the patients’ olfactory craving symptoms resolved. In this article, we reviewed English medical literature and the World Wide Web to determine if such olfactory cravings associated with iron deficiency anemia had been previously reported. We searched the PubMed, Google, and Google Scholar to find publications, reports, presentations, or testimonies of individuals in online blogs using a combination of search terms including “nasal,” “olfactory,” “smell,” “craving,” “iron deficiency,” and “anemia.” Although this specific symptom has only been previously published once in medical literature, we did find a large number of online patients self-reporting such a phenomenon potentially corroborating our practice experience. Upon further exploration using Google search engine, we came across a number of online blog posts, mostly in pregnancy blogs, in which participants described this unique symptom. These women reported powerful cravings of olfaction, and were frequently overtaken by a strong desire to smell certain odors. The types of substances craved and their associated medical conditions (when reported) are summarized in Supporting Information Table S1. The effects of IDA on the olfactory system have only been minimally explored. It is known that several key enzymes necessary for proper olfaction such as neuronal nitric oxide synthase, tryptophan dioxygenase, and tyrosine hydrolase require either heme or inorganic iron for structure or activity. In an animal study, iron-deficient rats were observed to have prolonged exploratory time (sniffing) for attractive odorants compared to controls. The hypothesis was that IDA decreased the activity of these enzymes resulting in a net reduction of inhibitory olfactory inputs. Another study compared the olfactory function of IDA patients with healthy subjects and found a heightened sensitivity (lower threshold) in detecting odorant among patients with IDA. These reports support a plausible association between the physiological changes in olfaction and iron store. The mystery behind the pathophysiology of this symptom is a driving factor for further research and exploration. Additionally, it would be interesting to investigate what factors potentially account for the discrepancy between the volume of reports seen in online blogs and those documented in clinical practice. Perhaps these symptoms are being overlooked or not screened for in clinical encounters, and therefore leading to a misunderstanding of this symptom in practice. By placing a name to this symptom, we hope to contribute to a better understanding and recognition of these olfactory cravings by both patients and physicians.