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Saturday, 26 October 2013

Neutropenia

Written for my twitter friend

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. Causes and Risk Factors
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).

A.2. Risk factors
1. H-ficolin
According to the study by the Department of Pediatrics, University of Bern, Bern, low concentration of H-ficolin was associated with an increased risk of FN, particularly FN with bacteraemia, in children treated with chemotherapy for cancer. Low H-ficolin thus represents a novel risk factor for chemotherapy-related infections(16).

2. Deficiency of mannose-binding lectin
Mannose-binding lectin-associated serine protease-2 (MASP-2) is an essential component of the lectin pathway of complement activation. According to the study by the University of Bern, MASP-2 deficiency was associated with an increased risk of FN in children treated with chemotherapy for cancer. MASP-2 deficiency represents a novel risk factor for chemotherapy-related infections(17).

3. Poison
Exposure to certain poison are associated to the increased risk of the disease(18).
According to the article of Delaware physician care, an aetna health plan, indicated the following risk factors(19).


4. Chemotherapy Regimen 
The aggressiveness of the chemotherapy regimen can be taken into account by giving to each individual drug a score (ranging from 0 to 4), according to its expected hem atological toxicity . For combination drug regimens, the regimen’s score is calculated by taking the mean of the individual agent’s weights. (Example: vinblastine + carboplatin = 5 ÷ 2= 2.5). A score ≥3 is considered high risk for neutropenia

5. Pre-existing neutropenia
a. Age >65 of age
b. Previous chemotherapy or radiation therapy
c. Advanced disease or uncontrolled cancer
d. Pre - existing n eutropenia, anemia or other cytopenias, or b one marrow involvement of tumor
e. Act ive Infection/open wounds, pneumonia, sepsis o Poor performance status (e.g., poor nutritional status, low albumin)
f. Renal impairment (GFR<30 or age >65 and elevated creatinine)
g. Liver dysfunction (elevated bilirubin, alkaline phosphatase)
h. Other serious co - morbidities (heart disease, hypertension, COPD)
i. Previous episodes of FN
g. A previous neutropenic complication in the immediate previous cycle with no plan to reduce dose intensity(19).

B. Symptoms
Neutrophilic granulocytes form the major type of leukocytes with counts ranging from about 1500-5000 cells/ micro l of blood under normal conditions. Neutrophils protect our body against bacterial and fungal infections. For this purpose, these cells are equipped with a machinery to sense the site of an infection and, upon local extravasation, rapidly move towards the site with invading micro-organisms, to ingest and kill them(20). The most common symptoms are
1. Fever
Fever during neutropenia (FN) is a frequent and potentially life-threatening complication of the treatment of childhood cancer, according to the Royal Children's Hospital Melbourne, Peter MacCallum Cancer Centre, Federal University of Sao Paulo, Alcuin College and Leeds Teaching Hospitals Trust(21).

2. Frequent infection symptoms can be resulted as
a. Mouth ulcers
b. Diarrhea
c. Burning sensation when urinating
d. Unusual redness, pain, or swelling around a wound, or
e. Sore throat
f. Abscesses
g. Rashes

C. Complications and diseases associated to Neutropenia
C.1. Complications
1. Unstable hemodynamic status, respiratory distress, altered mental status, newly developed arrhythmia that required intervention, and death
In the study to evaluate associations between the risk factors and serious complications in patients presenting to the ED with febrile neutropenia by reviewing the health information system database to identify a retrospective cohort of patients with febrile neutropenia who visited the ED of a tertiary medical hospital from January to December 2008, showed that serious complications during hospitalization were defined as unstable hemodynamic status, respiratory distress, altered mental status, newly developed arrhythmia that required intervention, and death during hospitalization.  Only episodes of febrile neutropenia caused by chemotherapy for underlying cancer were included(22).

2. High risk for septic complications
In the study to evaluate pentraxin 3 as a marker for complications of neutropenic fever in 100 hematologic patients receiving intensive chemotherapy with Pentraxin 3 and C-reactive protein measured at fever onset and then daily to day 3, showed that in comparison to C-reactive protein, pentraxin 3 achieved its maximum more rapidly. Pentraxin 3 correlated not only with the same day C-reactive protein but also with the next day C-reactive protein. High pentraxin 3 on day 0 was associated with the development of septic shock (P=0.009) and bacteremia (P=0.046). The non-survivors had constantly high pentraxin 3 levels(23).

C.2. Diseases associated to Neutropenia
Chronic neutropenia with autoimmune diseases is associated mainly with rheumatoid arthritis (RA), as Felty's syndrome or large granular lymphocyte (LGL) leukemia, and with systemic lupus erythematosus (SLE)(23a).
1.  Rheumatoid arthritis (RA) 
T cell large granular lymphocyte leukemia (T-LGL) is a disease characterized by clonal expansion of cytotoxic T cells (CTLs). It generally follows an indolent course and is notable for an association with chronic inflammation, neutropenia and rheumatoid arthritis (RA), according to the study by the Duke University Medical Center(24).

2. Felty’ssyndrome or large granular lymphocyte (LGL) 
Large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic cells, either CD3(+) (T-cell) or CD3(-) (natural killer, or NK). Both subtypes can manifest as indolent or aggressive disorders. T-LGL leukemia is associated with cytopenias and autoimmune diseases and most often has an indolent course and good prognosis. Rheumatoid arthritis and Felty syndrome are frequent, according to the study by Michal G. Rose, M.D., The Comprehensive Cancer Center (IIID), VA Connecticut Healthcare System(25).

3. Leukemia and related disorders
T-cell large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic T cells, which causes neutropenia, anemia, and/or thrombocytopenia. This condition is often associated with autoimmune disorders, especially rheumatoid arthritis, and other lymphoproliferative disorders(26).

4. Systemic lupus erythematosus (SLE)
In the study of 89 SLE patients (92% females), with their mean (SD) age and disease duration at the study entry of 31.7 (12.2) years and 2.4 (2.9) months, leukopenia was found at the diagnosis in 51.6% of the cases. The cumulative prevalence of leukopenia, lymphopenia, and neutropenia was observed in 57.3%, 96.6%, and 60.7%, respectively(27).

5. Crohn's disease
There is a report of a 29-year-old woman with a 20-year history of Crohn's disease and neutropenia. Because of repeated complications of Crohn's disease, she has undergone three intestinal resections and also has had recurrent skin abscesses, sinusitis, and pneumonia. Persistent neutropenia has been noted throughout the course of her disease, and antineutrophil antibodies have been detected in her serum and that of her younger brother, who also has Crohn's disease and neutropenia(28)

6. Graves' disease
There is a report of a 38-year-old man with Graves' disease taking propylthiouracil (PTU) for 6 years developed neutropenia and marked splenomegaly(29). 

7. Poikiloderma
Poikiloderma with neutropenia (PN, OMIM 604173) is a rare autosomal-recessive genodermatosis. Mutations in the C16orf57 gene have been recently identified as the cause(29a).

8. without serious complications in children with acquired neutropenia
In the study to to identify the relationship of acquired neutropenia with childhood infections and to assess its clinical course, complications, and outcome of 161 previously healthy children with febrile neutropenia/leukopenia aged (mean ± SD) 3.02 ± 3.86 years (range, 0.1-14). One hundred and thirty-six out of 161 patients (84.5 %) had transient neutropenia (TN), while in 25 patients, neutropenia was chronic (CN) and persisted for ≥180 days, indicated that a infectious agent was isolated in 98/161 (60.9 %) cases, in 68.4 % patients with TN, and in 20 % of those with CN (p = 0.001). Among the patients with CN, seven had positive antineutrophil antibodies (autoimmune neutropenia) and four were eventually diagnosed with hematological malignancy. In all age groups, TN was of short duration (<1 month), of mild to moderate severity, and was predominantly associated with viral infections. Two years after diagnosis, 143/161 children (88.8 %) were available for follow-up. One hundred and thirty-seven of 143 (95.8 %) had recovered completely, while the rest remained neutropenic(30).
  
D. Misdiagnosis and Diagnosis
D.1. Misdiagnosis
1. Kikuchi's disease
Kikuchi's disease is usually a self limiting illness characterised by pyrexia, neutropenia, and cervical lymphadenopathy particularly in young women of Asian descent. This often leads to an initial misdiagnosis of lymphoma(31).

2. Myeloid sarcoma of the spleen
There is a report of a 58-year-old woman presented with a 3-day history of fever and abdominal pain. The results of hematological work-up were consistent with acute myeloblastic leukemia (M2, French-American-British classification). Being susceptible to infection in this leukemic patient with severe neutropenia, a diagnosis of splenic abscess was straightforward, plausibly supported by the radiographic findings. Despite empiric broad-spectrum antibiotic treatment, hyperleukocytosis with resultant pulmonary leukostasis supervened. Histological sections from ultrasound-guided percutaneous core-needle biopsy of the spleen confirmed the diagnosis of myeloid sarcoma. However, delayed leukemia-targeted therapy, unfortunately, resulted in catastrophic mortality(32).

3. Acute myeloblastic leukemia M3v
Splenic abscesses in therapy-resistant acute myeloblastic leukemia presenting as recurrent febrile neutropenia and unresolved splenomegaly, according to the study by the Ankara Oncology Hospital(33).

4. Appendicitis
There is a report of a 13-year-old boy with acute myelogenous leukemia developed 2 episodes of febrile neutropenia during induction therapy. The second one was treated with a 5-day course of parenteral antimicrobial therapy, but the patient then presented with right lower quadrant abdominal tenderness, guarding, and rebound tenderness. Abdominal ultrasonography and computed tomography revealed appendicitis. Conservative medical management was unsuccessful, and appendectomy was performed 5 days after appendicitis was diagnosed(34).

D.2. Diagnosis
If you are experience of certain symptoms above, after a complete physical examination and recording family and health history, the tests which your doctor order may include
1. A complete blood count, or CBC
It is also known as  also known as full blood count (FBC) or full blood exam (FBE) or blood panel with an aim to check for information of the concentration of white blood cells, red blood cells, and platelets in the blood of a patient's blood

2. Bone Marrow biopsy
The procedure of bone marrow biopsy involves the use of a syringe to withdraw a sample of liquid bone marrow (aspiration) from the hip bone and then checking the samples for any abnormality of neutrophils.

Other tests may also be necessary, depending to the underlined causes of the diseases of which include(35)
4. Test for antineutrophil antibodies
5. Autoantibody screen, 
6. Vitamin B12 and folate assays
7. Acidified serum test, and tests for detecting systemic lupus erythematosus.  
E. Preventions
E.1. Diet to prevent Neutropenia
a. The Neutropenic diet, according to the article of The Neutropenic diet from Non Hopkin's lymphoma cyberfamily(36)
FOOD GROUPS
ALLOWED NOT ALLOWED
Dairy All pasteurized, grade "A" milk and milk products.
Commercially-packaged cheese and cheese products made with pasteurized milk (i.e. mild and medium cheddar, mozzarella, parmesan, Swiss, etc.)
Pasteurized yogurt
Dry, refrigerated, and frozen pasteurized whipped topping
Ice cream, frozen yogurt, sherbet, ice cream bars, homemade milkshakes
Commercial nutritional supplements and baby formulas, liquid and powdered
Unpasteurized or raw milk, cheese, yogurt, and other milk products
Cheeses from delicatessens
Cheeses containing chili peppers or other uncooked vegetables
Cheese with molds (i.e. blue, Stilton, Roquefort, gorgonzola)
Sharp cheddar, brie, camembert, feta cheese, farmer's cheese
Vegetables All cooked frozen or canned vegetables.
All cooked herbs and spices (add at least 5 minutes before end of cooking)
Raw vegetables, salads
Caesar Salads with Caesar dressing
Pepper
Garnishes
Uncooked herbs and spices
Fruits and Nuts Canned and frozen fruit and fruit juices
Thick skinned fruits (oranges, bananas)
Melons cut up and used immediately
Canned or bottled roasted nuts
Nuts in baked products
Commercially packaged peanut butter
Dried fruits
Raw fruit; foods containing raw fruits
Unpasteurized fruit and vegetable juices
Raw nuts
Roasted nuts in the shell
Precut fresh fruits
Bread, Grain, and Cereal Products All breads, bagels, rolls, pan-cakes, sweet rolls, waffles, French toast
Potato chips, corn chips, tortilla chips, pretzels, popcorn
Cooked pasta, rice, and other grain
All cereals, cooked and ready-to-eat
Raw grain products
Bakery breads, cakes, donuts, muffins
Potato/macaroni salad
Entrees, Soups All cooked entrees and soups All miso products (i.e. miso soup)
Meat and Meat Substitutes All well-cooked or canned meats (beef, pork, lamb, poultry, fish, shellfish, game, ham, bacon, sausage, hot dogs)
Well-cooked eggs (white cooked firm with thickened yolk acceptable, i.e. hard boiled, over hard)
Pasteurized egg substitutes (i.e. Egg Beaters)
Commercially-packaged salami, bologna, and other luncheon meats
Canned and commercially-packaged hard smoked fish, refrigerated after opening
Cooked tofu (which must be cut into 1" cubes or smaller and boiled a minimum of five minutes in water or broth before eating or using in recipes)
Raw or undercooked meat,, poultry, fish, game, tofu
Meats and cold cuts from delicatessen
Hard cured salami in natural wrap
Cold smoked salmon, lox
Pickled fish
Tempe (tempeh) products
Sushi
Raw oysters/clams
 
 
Beverages Tap water
Commercial bottled distilled and natural waters
All canned, bottled, powdered beverages
Instant and brewed coffee, tea; cold brewed tea made with boiling water
Brewed herbal teas using commercially-packaged tea bags
Commercial nutritional supplements, liquid and powdered
Well water (unless tested yearly and found safe)
Cold-brewed tea made with warm or cold water sun tea
Egg nog
Fresh apple cider 
Homemade lemonade
Spring water
Fats Oil, shortening
Refrigerated lard, margarine, butter
Commercial shelf-stable mayonnaise and salad dressings (including cheese-based salad dressings, refrigerated after opening)
Fresh salad dressings containing aged cheese (i.e. blue, Roquefort) or raw eggs, stored in refrigerated case
Desserts Refrigerated commercial and homemade cakes, pies, pastries, and pudding
Refrigerated cream-filled pastries
Homemade and commercial cookies
Shelf-stable cream-filled cupcakes (i.e. Twinkies, Ding Dong), fruit pies (i.e. Poptarts, Hostess frit pies), and canned pudding
Unrefrigerated cream-filled pastry products (not shelf-stable)
Cream or custard filled donuts
Other Salt, granulated sugar, brown sugar
Jam, jelly, syrups (refrigerated after opening)
Commercially-packaged (pasteurized) honey 
Catsup, mustard, BBQ sauce, soy sauce, other condiments (refrigerated after opening)
Pickles, pickle relish, olives (refrigerated after opening)
Raw or unpasteurized honey
Herbal and non-traditional (health food store) nutritional supplements, Chinese herbs
Brewers yeast, if eaten uncooked
But according to the study by the New York University, despite improved survival of children with cancer, opportunistic infections remain a significant cause of morbidity and mortality in this population. Several interventions have been tried to decrease the incidence of infection by reducing patients' exposure to bacteria during neutropenia. The neutropenic diet is one such intervention that was intended to limit the introduction of bacteria into the host's gastrointestinal tract. The only studies evaluating this diet have used this strategy in combination with multiple other interventions, and the independent effect of this diet remains unknown(37). Other in the study to demonstrate a safe and feasible methodology to evaluate the infection rate in pediatric cancer patients randomized to the neutropenic diet or to Food and Drug Administration (FDA)-approved food safety guidelines with pediatric oncology patients receiving myelosuppressive chemotherapy randomized to the neutropenic diet or to FDA food safety guidelines and followed through one chemotherapy cycle found that four patients on each diet arm developed febrile neutropenia. The adherence rate was 94% for the neutropenic diet and 100% for the food safety guidelines. Although patients were able to tolerate both diets, there was more reported difficulty adhering to the neutropenic diet. Infection rates for children with cancer on the neutropenic diet were similar to those for patients following food safety guidelines(38).

b. Foods to enhance immune system
One of the most notable changes in the 2006 guidelines is that the level of risk when preventive use of blood cell growth factors is justified has been lowered. Previously, preventive use of blood cell growth factors was recommended for patients who had at least a 40% risk of developing febrile neutropenia. The 2006 guidelines recommend preventive use of blood cell growth factors for patients whose risk of febrile neutropenia is 20% or higher.
b.1. Green tea
Consuming green tea or its active ingredient, epigallocatechin-3-gallate (EGCG), has been shown consistently to benefit the healthy functioning of several body systems. In the immune system specifically, accumulating evidence has revealed an immunomodulating effect of green tea/EGCG. Several types of immune cells in both the innate and adaptive immune systems are known to be affected in varying degrees by green tea/EGCG. Among them, the dramatic effect on T cell functions has been repeatedly demonstrated, including T cell activation, proliferation, differentiation, and production of cytokines, according to the study by the Harvard Medical School(39).

b.2. Garlic
In the study to evaluate the immunostimulatory activities such as cell proliferation, tumor necrosis factor (TNF-α) and nitric oxides (NO) production of raw garlic and black garlic extracts on individual primary lymphocytes or macrophages isolated from the blood of 21 volunteers indicated that the immunostimulatory activities of RGE and BGE can be strongly correlated with the antioxidant and anticancer activities. Determination of immunostimulatory activities of different types of garlic using immune cells isolated from volunteers was dependent on the individual constituents due to changes in the composition of garlic during processing. Individual primary immune cells might be used as important tools to determine individual differences in all food ingredients for the development of personalized immunostimulatory active foods(40).

3. Turmeric and ginger
According to the study by the Assam University, polar fractions of C. longa and Z. officinale rhizomes boost the immune system by altering the cytokine milieu of the immunosuppressed macrophages, thus modulating their functional status. Therefore, it can be inferred that dietary intake of C. longa and Z. officinale potentiates the non-specific host defenses against opportunistic infections(41).

4.  Tomato
In the study to examine the effects of lycopene found abundantly in tomato, on the oxidative injury and immunity activities of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer rats, showed that dministration of lycopene to gastric carcinoma-induced rats largely up-regulated the redox status and immunity activities to decrease the risk of cancer. up-regulation of antioxidants and immunity by lycopene treatment might be responsible for the anticancer effect in gastric carcinoma(42).


E.2. Phytochemicals to prevent Neutropenia
1. Epigallocatechin-3-gallate
One of the proposed health benefits of consuming green tea is its protective effect on autoimmune diseases. Research on the immunopathogenesis of autoimmune diseases has made significant progression in the past few years and several key concepts have been revised. T cells, particularly CD4(+) T helper (Th) cells, play a key role in mediating many aspects of autoimmune diseases. Upon antigenic stimulation, naïve CD4(+) T cells proliferate and differentiate into different effector subsets. Th1 and Th17 cells are the pro-inflammatory subsets of Th cells responsible for inducing autoimmunity whereas regulatory T cells (Treg) have an antagonistic effect. Green tea and its active ingredient, epigallocatechin-3-gallate (EGCG), have been shown to improve symptoms and reduce the pathology in some animal models of autoimmune diseases(43)

2. Allicin 
Allicin treatment enhanced the production of pro-inflammatory mediators such as IFN-γ, TNF, IL-12p70 and NO. The absolute numbers of CD4+ T cells, DCs and macrophages were significantly higher in allicin-treated mice. In addition, allicin promoted the maturation of CD11c+ DCs, whereas it did not cause major changes in IL-4 and the level of anti-inflammatory cytokine IL-10(44).

3. Curcumin
In the study to investigate the bioavailablity of a well-established dietary antiinflammatory, curcumin, and examines its effect on adaptive immunity, found that long-term, low-dose, oral consumption of curcumin activates peroxisome proliferator-activated receptor-gamma, deactivates type 1 response, inhibits inducible nitric oxide synthase, and interferes with adaptive immunity to exacerbate the pathogenesis of Leishmania donovani infection in vivo. These in vivo effects can be correlated to activities on infected residential macrophages in vitro. Therefore, when reactive radicals generated from inflammation play the dominant role in elimination of pathogens, excessive use of the antioxidative supplements may compromise microbial defense(45).

4. Carotenoids
In the study to investigate the effects of orally administered carotenoids from natural sources on the non-specific defense mechanisms of rainbow trout in a nine-week feeding trial, showed that dietary carotenoids from both D. salina and P. rhodozyma can modulate some of the innate defense mechanisms in rainbow trout(46).

E.3. Antioxidant to prevent Neutropenia
1. Selenium  
Dietary selenium (]Se), mainly through its incorporation into selenoproteins, plays an important role in inflammation and immunity. Adequate levels of Se are important for initiating immunity, but they are also involved in regulating excessive immune responses and chronic inflammation. Evidence has emerged regarding roles for individual selenoproteins in regulating inflammation and immunity, and this has provided important insight into mechanisms by which Se influences these processes, according to the study by the University of Hawaii(47).

2. Vitamin D and C 
Inflammatory responses are operationally characterized by pain, redness, heat and swelling at the site of infection and trauma. Mast cells reside near small blood vessels and, when activated, release potent mediators involved in allergy and inflammation. Vitamin D modulates contraction, inflammation and remodeling tissue. Therapy targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions.  Vitamin C is also an anti-oxidant well-known as an anti-scurvy agent in humans. Vitamin C inhibits peroxidation of membrane phospholipids and acts as a scavenger of free radicals and is also required for the synthesis of several hormones and neurotransmitters. In humans, vitamin C reduces the duration of common cold symptoms, even if its effect is not clear. Supplementation of vitamin C improves the function of the human immune system, such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis and delayed-type hypersensitivity(48).

3. Zinc
T cell functions were affected adversely even when the deficiency of zinc was mild in humans. Characteristically during zinc deficiency, the serum thymulin activity (a thymic hormone) was decreased which was restored following zinc supplementation. Our studies also showed that zinc deficiency caused an imbalance between TH1 and TH2 functions. The production of IFN-g, IL-2, TNF-a (products of TH1 cells) were decreased, whereas the production of IL-4, IL-6 and IL-10 (products of TH2) were not affected during zinc deficiency. T cell subpopulation studies revealed that the CD4+ CD45RA+ to CD4+ CD45RO+ ratio was decreased as a result of zinc deficiency, suggesting that zinc may be required for the regeneration of new CD4+ T cells. zinc deficiency decreased NK cell lytic activity and caused a decrease in the percentage of CD8+ CD73+ T cells which are known to be predominantly precursors of cytotoxic T cells. In a suitable cell culture model our studies revealed that the gene expression of a DNA synthesizing enzyme TK was affected adversely which resulted in delayed cell cycle and decreased cell growth(49).

4. Resveratrol
In the study to evaluate the immune modulating effect of low dose of resveratrol by the
Chinese Academy of Sciences, showed that resveratrol (0.75-6 micromol/L) concentration-dependently promoted lymphocyte proliferation and IL-2 production induced by ConA. Sac induced IL-12 and IFN-gamma (interferon type II) production were also concentration-dependently enhanced by resveratrol, while IL-10 production was inhibited. Resveratrol (4 mg/kg, ig) promoted DTH response of mouse, which was suppressed by ethanol (16 %, w/v) consumption(50).

F. Treatments
F.1. In conventional medicine perspective
F.1.2. Treatments is depending to the underlined causes of the disease, patient with Neutropenia are advised to the lists of below
1. Good oral hygiene and dental care
According to the study in a report of clinical periodontal findings and microflora profiles of 2 children, 1 with severe congenital neutropenia (SCN, Kostmann type) and 1 with cyclic neutropenia (CN), by the Hiroshima University Faculty of Dentistry showed that Use of 1% povidone iodine solution and local antibiotic application under supervised oral hygiene were helpful to improve gingival conditions in patients with chronic neutropenia(51). Other study indicated that in the study of Benign familial neutropenia (BFN), it is a condition where there is a decrease in circulating neutrophils in the blood and patients suffer from oral manifestations which include: persistant periodontal disease, recurrent neutropenic ulceration and candidal infections(52).

2. Others according to the article of WebMD and Medscape include
2.1. WebMD(53)
a. Avoiding contact with sick people
b. Always wearing shoes
c. Cleaning cuts and scrapes, then covering them with a bandage
d. Using an electric shaver rather than a razor
e. Avoiding animal waste and, when possible, not changing infants' diapers
f. Avoiding unpasteurized dairy foods; undercooked meat; and raw fruits, vegetables, grains, nuts, and honey
g. Staying out of hot tubs, ponds, and rivers

2.2. Medscape(54)
a. Remove any offending drugs or agents in cases involving drug exposure: If the identity of the causative agent is not known, stop administration of all drugs until the etiology is established
b. Use careful oral hygiene to prevent infections of the mucosa and teeth
c. Avoid rectal temperature measurements and rectal examinations
d. Administer stool softeners for constipation
e. Use good skin care for wounds and abrasions: Skin infections should be managed by someone with experience in the treatment of infection in neutropenic patients.

F.2.2.  Types of therapy depending to the underlined causes of the disease but not limit to include
1. Corticosteroids 
Corticosteroids is the synthetic form of cortisol produced hat your adrenal glands produce naturally.
The aims of the medicine is to reduce autoantibody production, There is a report of a case of neutropenia in an infant, associated with repeated minor infections which responded to treatment with antibiotics. A granulocyte agglutinin was detected in the serum. Following treatment with prednisolone the neutropenia remitted, the antibody disappeared and the infections ceased(55).

2. Antibiotics 
There is a report by the Urmia University of Medical Sciences, of a 22-year-old male with idiopathic autoimmune thrombocytopenia whose diagnosis was made at age of eight. He underwent splenectomy at age ten and ITP recurred at age 21 with episodes of infection and severe neutropenia (absolute count around 170/μl). He showed no response to immunoglobulin, corticosteroids, danazol, cyclosporine and azathioprine. Anti-CD20 antibody was administered at a dose of 375 mg/m(2) once a week for 2 weeks. After the second infusion of rituximab, the platelet count increased from 4,000 to 516,000/mm(3) and neutrophils count raised from 180 to 545/mm(3). The response improvement persisted during follow up for 9 months (neutrophil count 4,390/mm(3))(56).
 
3. Granulocyte colony-stimulating factor (G-CSF) 
Granulocyte colony-stimulating factor (G-CSF) also known as colony-stimulating factor 3 (CSF 3), is a proteins that contain oligosaccharide chains (glycans) used to stimulate the bone marrow in production of granulocytes and stem cells and release them into the bloodstream. In a report of a  treated a case of autoimmune neutropenia in a 57-year-old, by the  Kyushu University, because neutropenia persisted despite the administration of prednisolone for 30 days, daily subcutaneous injection of human recombinant granulocyte colony-stimulating factor (rhG-CSF) at a dosage of 100 micrograms was started. Neutrophil count increased gradually and reached a plateau of 5,000/microliters by day 25 after administration of rhG-CSF(57).

4.  Intravenous immunoglobulin therapy
Intravenous immunoglobulin (IVIG) is an immunomodulating agent that induces beneficial therapeutic responses in children and adults. IVIG is not only used for prophylaxis and therapy of infections in patients with primary and secondary immunodeficiencies associated with defective antibody production, but also used for treatment of patients with systemic inflammatory disorders, autoimmune diseases, and neuroimmunologic conditions(58).  There is a report of a young woman presenting respiratory infections, polyarthritis, severe neutropenia, and increased serum IgM was treated with intravenous immunoglobulin (IVIG) with good clinical and laboratory outcome followed by a loss of efficacy(59). Other in the study of performed serial hematology, including differentiation of white blood cells (WBC), before and after 22 instances of IVIG in 16 patients with neuroimmunologic disorders indicated that WBC and neutrophils showed a significant decrease with a nadir 2 days after IVIG, but returned to previous values by 14 days with no treatment except in 2 cases. No patient showed any infectious complication(60).

5. Supplements for patients with Copper, Vitamin B12, Folate deficiency
 
F.2.3. Treatment depending to types of Neutropenia
1. Severe autoimmune neutropenia
According to the study by the,in the study to systematically review the clinical presentations and management of periodontitis patients with neutropenia and present a patient with severe autoimmune neutropenia of twenty-four case reports describing a total of 33 patients, showed that improvements in periodontal condition were observed in 86% of patients who were administered adjuvant systemic antibiotics compared to 47% of patients who were not given supplemental therapy. Granulocyte-colony stimulating factor was administered to 67% of the neutropenic patients, and both improvement and progression of the hematological condition were monitored. Scaling and root planing, in combination with systemic antibiotics to supplement therapy for the underlying disease, have been successful in most cases(61).

2. Febrile neutropenia
Febrile neutropenic patients are at greater risk of getting bacterial and fungal infections. Empirical antifungal therapy is considered if the fever persists despite broad-spectrum antibiotics including vancomycin, According to the study by the Postgraduate Institute of Medical Education and Research,  to determine the response of empirical amphotericin B deoxycholate (dAMB) starting either on day 4 or day 8 in febrile neutropenic patients not responding to broad-spectrum antibiotics and without localisation of fever. Fifty-six patients with persistent neutropenic fever despite 72 h of antibiotic therapy were randomly assigned to receive dAMB either starting on day 4 (group A, n = 27, median age 23 years) or starting on day 8 (group B, n = 29, median age 25 years). Satisfactory response (patient remaining afebrile for 48 h and maintaining absolute neutrophil count >500 μl-1 ) occurred in 85.2% of patients in group A vs. 69.5% in group B (P = 0.209). Patients in group A took significantly fewer days to become afebrile than group B (5.4 ± 3.9 days vs. 11.3 ± 4.0 days, P = 0.0001). The adverse side effects of dAMB (nephrotoxicity, hypokalemia and hypomagnesemia) occurred at similar rates in both groups. Early addition of empirical dAMB in febrile neutropenic patients leads to their early defervescence and decreased dose requirement(62).

2. Treatment of Neutropenia as a result of chemotherapy in cancer patients
Cytotoxic chemotherapy suppresses the hematopoietic system, impairing host protective mechanisms and limiting the doses of chemotherapy that can be tolerated. Neutropenia, the most serious hematologic toxicity, is associated with the risk of life-threatening infections as well as chemotherapy dose reductions and delays that may compromise treatment outcomes.  According to the study by the University of Rochester School of Medicine and Dentistry, Neutropenia represents a major dose-limiting toxicity of chemotherapy and is associated with an increased risk of infection, impaired patient quality of life, and interference with the delivery of full-dose chemotherapy. These complications increase not only morbidity and mortality associated with cancer treatment but also the overall cost of care for cancer patients. Conversely, chemotherapy-induced neutropenia as a surrogate for delivered dose intensity has been associated with improved cancer survival. Administration of myeloid growth factors, such as filgrastim and pegfilgrastim, reduces the risk for neutropenic complications and facilitates the delivery of full-dose chemotherapy. There is an ongoing effort to identify patients at increased risk for developing neutropenic complications who would likely benefit from preemptive myeloid growth factor therapy. Appropriate use of myeloid growth factors is associated with reduced neutropenic complications, improved patient quality of life, and potentially improved disease control and long-term survival(63).

3. Cyclic neutropenia
In the study of six patients with cyclic neutropenia treated with recombinant human granulocyte colony-stimulating factor (G-CSF) for 3 to 15 months, found that uring the first 40 months of treatment, no typical mouth ulcers or bacterial infections occurred; recurrent gingivitis improved. We conclude that G-CSF is effective for the treatment of cyclic neutropenia in humans(64).

4. Congenital neutropenia
In recent years, the converging efforts of hematologists, immunologists and geneticists have led to the discovery of the genetic and biochemical basis of severe congenital neutropenia; cyclic neutropenia; warts, hypogammaglobulinemia, immunodeficiency, myelokathexis or WHIM syndrome and other rarer conditions associated to neutropenia. According to the study by the University of Brescia, although the diagnosis of congenital neutropenia includes many disorders of distinct origin and variable prognosis, their treatment is still based on granulocyte colony stimulating factor administration. Understanding the pathogenesis of these forms of neutropenia and their evolution will focus future studies on the mechanisms of normal and pathological myelopoiesis and on the development of the most appropriate treatment for each type of neutropenia(65). But other researchers indicated that the treatment with G-CSF is not sufficient to correct all of the functional deficiency of neutrophils, and this might account for the consistent risk of infections observed in SCN patients(66).

F.2. In Herbal medicine perspective
1. Glycyrrhizin
Glycyrrhizin is a ingredient found in liquorice (alt. licorice) rootIn the study to evaluate effect of glycyrrhizin on immunity function in allergic rhinitis (AR) mice, found that glycyrrhizin can improve immunity function in AR mice, suggesting a potential drug for the prevention and therapy of AR(67).

2. Bayberry bark extract, tea
Myricetin is a naturally occurring flavonoid that is found in many fruits, vegetables, teas and medicinal herbs, including Bayberry bark. In the study to evaluate the potential for myricetin to modulate lipopolysaccharide (LPS)-stimulated activation of mouse bone marrow-derived DCs, showed that treatment with myricetin up to 10 µg mL(-1) does not cause cytotoxicity in cells. Myricetin significantly decreased the secretion of tumour necrosis factor-α, interleukin-6 and interleukin-12p70 by LPS-stimulated DCs. The expression of LPS-induced major histocompatibility class II, CD40 and CD86 on DCs was also inhibited by myricetin, and the endocytic and migratory capacity of LPS-stimulated DCs was blocked by myricentin. In addition, LPS-stimulated DC-elicited allogeneic T-cell proliferation was reduced by myricetin. Moreover, our results confirmed that myricetin attenuates the responses of LPS-stimulated activation of DCs via suppression of IκB kinase/nuclear factor-κB and mitogen-activated protein kinase-dependent pathways(68).

3. Rabdosia rubescens
According to the study of Shanghai Jiao Tong University School of Medicine, oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells. Intriguingly, the t(8;21) product AML1-ETO (AE) fusion protein, which plays a critical role in leukemogenesis, The ectopic expression of AE enhanced the apoptotic effect of oridonin in U937 cells. Preincubation with caspase inhibitors blocked oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues 188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin prolonged lifespan of C57 mice bearing truncated AE-expressing leukemic cells without suppression of bone marrow or reduction of body weight of animals, and exerted synergic effects while combined with cytosine arabinoside. Oridonin also inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1 cells(68a).
 
F.3. In traditional Chinese medicine perspective 
1. Herbal extract granules
In the study applied the highest standard of clinical trial methodology to examine the role of CHM in reducing chemotherapy-induced toxicity, while maintaining a tailored approach to therapy with one hundred and twenty patients were accrued at the time of premature study termination. Enrolled patients were randomly assigned to one of three Chinese herbalists who evaluated and prescribed a combination of single-item packaged herbal extract granules. Patients received either CHM or placebo packages with a corresponding serial number. The placebo package contained nontherapeutic herbs with an artificial smell and taste similar to a typical herbal tea. The primary end points were hematologic and non-hematologic toxicity according to the National Cancer Institute Common Toxicity Criteria Version found that patient characteristics of the two groups were similar. The incidence of grade 3/4 anemia, leukopenia, neutropenia, and thrombocytopenia for the CHM and placebo groups were 5.4%, 47.3%, 52.7%, and 1.8% and 1.8%, 32.2%, 44.7%, and 3.6%, respectively (P = 0.27, 0.37, 0.63, and 0.13, respectively). Incidence of grade 2 nausea was the only non-hematologic toxicity that was significantly reduced in the CHM group (14.6% versus 35.7%, P = 0.04)(69).

2. Lycium barbarum polysaccharide (LBP)
In the study to nvestigate the therapeutic effects of Lycium barbarum polysaccharide (LBP) on mitomycin C (MMC)-induced myelosuppressive mice, found that LBP at 100 mg/kg (LBP-L) on day 14 and LBP at 200 mg/kg (LBP-H) on days 10, 14, 17, 19 and 21, significantly ameliorated the decrease of peripheral RBC, HGB and hematocrit (HCT) of myelosuppressive mice compared to the control. LBP-L on days 12 and days 14 and LBP-H on days 10, 12, 14, 17, 19 and 21, significantly enhanced peripheral PLT recovery of myelosuppressive mice compared to the control. LBP-H on days 12, 17, 19 and 21, significantly inhibited the increase of mean platelet volume (MPV) of myelosuppressive mice compared to the control. LBP showed no obviously effect on neutropenia induced in mice by MMC(70).

3.  Fu Zheng and the Gong Xiao
In the study of observed the effect of chemotherapy combined with Chinese herbs and western drugs on white blood cell count in 31 patients with gastric cancer with patients were divided into 3 groups: (1) Fu Zheng (strengthen the body resistance) with invigorating the Spleen and Kidney recipe; (2) Fu Zheng with western drugs raising WBC and enhancing immunity; (3) Gong Xiao (eliminating the evil factors and mass) with promoting blood circulation to remove blood stasis recipe or eliminating the evil factors and mass recipe, suggested that invigorating the Spleen and Kidney recipe had specific effect on decreasing the toxicity and side effect of chemotherapy, preventing bone marrow suppression and leukopenia, and was better than western drugs used in group II. It showed in the treatment of cancer with TCM, we must pay attention to the relationship between the Fu Zheng and the Gong Xiao(71). 

3. Chinese herbal medicine
In the study to evaluate traditional Chinese medicine (TCM) in improving quality of life (QOL), reducing chemotoxicity and modulating immune function in patients undergoing chemotherapy, found that there was no significant difference in the GHS between the two groups. With adjustment for stage, chemotherapy type, disease status, age and baseline value, emotional function, cognitive function and nausea and vomiting were found to be worse or less improved in the TCM group compared with placebo group after six cycles of chemotherapy. The TCM group had less neutropenia after three cycles (0% grade 4 neutropenia versus 28.6%). There were no other significant differences in terms of chemotoxicity. Lymphocyte counts and cytokine activities decreased less in the TCM group(72).
 Other inthe searching of The Cochrane Breast Cancer Specialised Register (15/02/2007), The Cochrane Central Register of Controlled Trials (CENTRAL); (The Cochrane Library 2006, Issue 4); MEDLINE (1966 to December 2006); EMBASE (1990 to December 2006); and Chinese Biomedical Literature (2006, Issue 4), indicated that the searching provides limited evidence about the effectiveness and safety of Chinese medicinal herbs in alleviating chemotherapy induced short term side effects. Chinese medicinal herbs, when used together with chemotherapy, may offer some benefit to breast cancer patients in terms of bone marrow improvement and quality of life, but the evidence is too limited to make any confident conclusions(73).

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