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Thursday, 5 December 2013

Neutropenia - The Causes

Neutropenia is defined as a condition of  abnormally low number of neutrophils, as a  result of granulocyte disorder of that leads to Immunodeficiency with lower than normal  circulating white blood cells. Patients with neutropenia are susceptible to bacterial infections causes of neutropenic sepsis.
Neutropenia is either problems in the production of the cells by the bone marrow and destruction of the cells from somewhere else in the body, if  neutrophil count falls below 1,000 cells per microliter of blood.
Neutropenia can be classified into acute and chronic types, depending to the duration of the illness. Some researchers divided severity of the disease, depending to the absolute neutrophil count (ANC) and is described as follows(a).
1. Mild neutropenia, when the ANC falls below a lower limit of 1500 per mm3 (1.5 x 109 /1), but remains higher than 1000 per mm3 (1.0 x 109 /1).
2. Moderate neutropenia, when the ANC falls between 500 per mm3 and 1000 per mm3 (0.5 x 109 /1 - 1.0 x 109 /1)
3. Severe neutropenia, when the ANC falls below 500 per mm3 (0.5 x 109 /1)

A.1.  Causes
1. Decreased production in the bone marrow
a. Aplastic anemia  
According to the study by the Jichi Medical University, patients with aplastic anemia (AA) or myelodysplastic syndrome (MDS) often have persistent severe neutropenia and are susceptible to infectious complications(1).

b. Arsenic poisoning   
There is a report of a case of the death by arsenic poisoning of a 62-year-old white man is presented. One year prior to death, he developed intermittent bouts of severe gastroenteritis with vomiting and diarrhea, hyperpigmentation and keratosis of the skin, neutropenia, and Guillain-Barré-like neuropathy for which he was hospitalized several time(2).

c. Cancers
In the study to determine the impact of primary prophylactic colony-stimulating factor (CSF) use on febrile neutropenia in a large patient population receiving contemporary chemotherapy regimens to treat breast cancer, colorectal cancer, or non-small cell lung cancer (NSCLC), showed that of the 998 patients with breast cancer, 72 (7.2%) experienced febrile neutropenia, 28 of whom received primary prophylactic CSF. In the patients with breast cancer, we observed that primary prophylactic CSF use was associated with reduced febrile neutropenia rates; however, the analysis may have been confounded by unmeasured factors associated with febrile neutropenia(3).

d. Hereditary disorders   
Certain prenatal conditions can be result of Neutropenia
d. 1. Homozygous G6PC3 mutations
Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects, according to the study by the Memorial University of Newfoundland(4).

d.2. Hematologic condition
There is a report results for six patients with Severe congenital neutropenia (SCN) who underwent Hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) between 1997 and 2001 at two transplant centers. Two patients transplanted for MDS survived. Both of these patients were transplanted without being given induction chemotherapy. Four patients, who all received induction chemotherapy for AML prior to HSCT, died. Administering induction chemotherapy prior to HSCT resulted in significant morbidity(5).

d.3. Cyclic neutropenia
there is a report of a 22 years old patient presented with recurrent episodes of diarrhoea, pharyngitis, apthous ulcers and fever for the past 6 months. The patient was admitted and blood studies revealed neutropenia with increased number of Large Granular Lymphocytes.  Later on it was found out that his neutrophil count dropped to less than 0.2 x 10(9)/L after every 3 weeks. Bone marrow study revealed decreases neutrophil precursors during these episodes. He was diagnosed with adult onset cyclic neutropenia and his episodes were treated with G-CSF and Ceftriaxone, according to the Medical Ward-D, Khyber Teaching Hospita(6).

d.4, HAX1 deficiency
HAX1 is a major regulator of myeloid homeostasis and underline the significance of genetic control of apoptosis in neutrophil development.(6a).


e. Copper, Vitamin B12, Folate deficiency
e.1. Copper deficiency
Copper deficiency is an under-recognized cause of reversible refractory anemia and leukopenia, particularly neutropenia, often misdiagnosed as myelodysplastic syndrome (MDS)(7).

e.2. Vitamin B12 and Folate deficiency
Women with breast carcinoma were asked to complete a questionnaire that recorded their use of dietary supplements. Blood samples were obtained for the assessment of serum vitamin B12 and folate levels before and after the first cycle of chemotherapy and for weekly complete blood counts, according to the study by the University of Vermont(8).

2. Increased destruction in the bone marrow
a. Autoimmune neutropenia
Antineutrophil antibodies are well recognized causes of neutropenia, producing both quantitative and qualitative defects in neutrophils and increased risk for infection. In primary autoimmune neutropenia (AIN) of infancy, a moderate to severe neutropenia is the sole abnormality; it is rarely associated with serious infections and exhibits a self-limited course. Chronic idiopathic neutropenia of adults is characterized by occurrence in late childhood or adulthood, greater prevalence among females than among males, and rare spontaneous remission. Secondary AIN is more commonly seen in adults and underlying causes include collagen disorders, drugs, viruses and lymphoproliferative disorders, according to the study by the University of Milan(9).  
b. Chemotherapy-induced neutropenia
Thirty-two patients on treatment for solid cancers who were admitted with febrile neutropenia between January and December 2010, according to the Cambridge University Hospitals NHS FoundationTrust(2).
There is a study indicated that chemotherapy-induced febrile neutropenia in the inpatient and outpatient settings for a solid tumor or non-Hodgkin's lymphoma(10).

3. Medication induced neutropenia
According to the study by the University Hospital of Strasbourg, over the last 20 years, the incidence of idiosyncratic drug-induced agranulocytosis or acute neutropenia has remained stable at 2.4-15.4 cases per million, despite the emergence of new causative drugs: antibiotics (beta-lactam and cotrimoxazole), antiplatelet agents (ticlopidine), antithyroid drugs, sulfasalazine, neuroleptics (clozapine), antiepileptic agents (carbamazepine), nonsteroidal anti-inflammatory agents and dipyrone. Drug-induced agranulocytosis remains a serious adverse event due to the occurrence of severe sepsis with severe deep infections (such as pneumonia), septicemia and septic shock in around two thirds of patients(11).

4. Hemodialysis
Neutropenia and degranulation of neutrophils during hemodialysis with cellulosic membranes have been linked to complement activation, whereas in the synthetic polymethyl methacrylate (PMMA) membrane, degranulation occurs without notable complement activation, according to the study by the University of Freiburg(12).

5. Bacteria and viral infections
a. Bacteria infection
The College of Medicine, Korea University, reported of a 259 cases of febrile neutropenia occurring in 137 patients with hematologic disease(13). Also according to the Universidad Pontificia Bolivariana, in the study of 101 episodes of FN in 43 patients with the median age was 44 years. 63.5% of patients had no apparent clinical focus of infection at admission, 11.8% had soft tissue compromise and 8.9% urinary tract infection. Bacteremia was documented in 41.5% and catheter-associated bacteremia in 3.9%. The most common organisms were Escherichia coli 43.4%, Klebsiella pneumoniae 17.3% and Staphylococcus aureus 8.6%. Of those isolated in blood 84.7% were Gram negative rods and 15.2% were Gram positive bacteria. Piperacillin/tazobactam was the most common empirically prescribed antibiotic (81.1%). Mortality of FN episodes occurred in 8 (7.92%) patients, 5 (62.5%) attributable to infection and 3 (37.5%) due to progression of hematologic malignancy with a resolution of FN(14).

b. Viral infections 
Patients with hematological malignancies and therapy induced neutropenia (n = 159) were screened regarding a broad range of common respiratory viruses in the nasopharynx and for viruses commonly detected in severely immunosuppressed patients in peripheral blood. Quantitative PCR was used for detection of viruses. A viral pathogen was detected in 35% of the patients. The detection rate was rather similar in blood (22%) and NPA (18%) with polyoma BK virus and rhinovirus as dominating pathogens in blood and NPA, respectively. Patients with chronic lymphocytic leukemia (CLL) (p<0.01) and patients with fever (p<0.001) were overrepresented in the virus-positive group(15).
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Sources
(a) http://www.neutropenia.ca/about/what-is-neutropenia
(1) http://www.ncbi.nlm.nih.gov/pubmed/21692099 
(2) http://www.ncbi.nlm.nih.gov/pubmed/2220708
(3) http://www.ncbi.nlm.nih.gov/pubmed/22392824
(4) http://www.ncbi.nlm.nih.gov/pubmed/23171239
(5) http://www.ncbi.nlm.nih.gov/pubmed/15640815 
(6) http://www.ncbi.nlm.nih.gov/pubmed/22764469
(6a) http://www.ncbi.nlm.nih.gov/pubmed/17187068
(7) http://www.ncbi.nlm.nih.gov/pubmed/22080848  
(8) http://www.ncbi.nlm.nih.gov/pubmed/15329916
(9) http://www.ncbi.nlm.nih.gov/pubmed/16207350 
(10) http://www.ncbi.nlm.nih.gov/pubmed/23824496
(11) http://www.ncbi.nlm.nih.gov/pubmed/18043241 
(12) http://www.ncbi.nlm.nih.gov/pubmed/8785392 
(13) http://www.ncbi.nlm.nih.gov/pubmed/19762083.
(14) http://www.ncbi.nlm.nih.gov/pubmed/23677158 
(15) http://www.ncbi.nlm.nih.gov/pubmed/22570724