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==Overview==
==Overview==
'''Neutropenia''' is a [[Hematology|hematological]] disorder characterized by an abnormally low number of [[neutrophil granulocyte]]s (a type of [[white blood cell]]). Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against [[infection]]s by destroying [[bacterium|bacteria]] in the [[blood]]. Hence, patients with neutropenia are more susceptible to bacterial infections and without prompt medical attention, the condition may become life-threatening. Neutropenia can be [[Acute (medical)|acute]] or [[chronic (medicine)|chronic]] depending on the duration of the illness. A patient has chronic neutropenia if the condition lasts for greater than 3 months. It is sometimes used interchangeably with the term [[leukopenia]]. However, neutropenia is more properly considered a subset of leukopenia as a whole. Some patients, such as those with constitutional/benign ethnic neutropenia, suffer relatively few complications, however neutropenia related to cytotoxic chemotherapy, [[hematopoietic stem cell]] transplant, or other causes of bone marrow suppression may present as a medical emergency.
'''[[Neutropenia]]''' is a [[Hematology|hematological]] disorder characterized by an abnormally low number of [[neutrophil granulocyte]]s (a type of [[white blood cell]]). Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against [[infection]]s by destroying [[bacterium|bacteria]] in the [[blood]]. Hence, patients with neutropenia are more susceptible to bacterial infections and without prompt medical attention, the condition may become life-threatening. Neutropenia can be [[Acute (medical)|acute]] or [[chronic (medicine)|chronic]] depending on the duration of the illness. A patient has chronic neutropenia if the condition lasts for greater than 3 months. It is sometimes used interchangeably with the term [[leukopenia]]. However, neutropenia is more properly considered a subset of leukopenia as a whole. Some patients, such as those with constitutional/benign ethnic neutropenia, suffer relatively few complications, however neutropenia related to [[cytotoxic]] [[chemotherapy]], [[hematopoietic stem cell]] transplant, or other causes of [[bone marrow suppression]] may present as a medical emergency.
== Classification ==
Calculated based on blood count differential, neutropenia is defined as an absolute neutrophil count (ANC) less than 1,500 cells per microliter and is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (including both mature neutrophils and band forms).


- '''Mild Neutropenia:''' ANC 1,000-1500 cells/microliter
==Historical Perspective==
[[Neutropenia]] was first noted around the start of the 20th century on review of blood cell differentials described in patients with [[lupus]], other [[autoimmune disorders]], and with various drug toxicities.<ref name="NLMID39120200R">{{cite journal |author=Dameshek W. |title=Leukopenia and Agranulocytosis.|journal=Oxford University Press. |volume=1|pages=841-52|year=1944|NLM ID 39120200R}}</ref>


- '''Moderate Neutropenia:''' ANC 500-1000 cells/microliter
==Classification==
Calculated based on blood count differential, neutropenia is defined as an [[absolute neutrophil count]] (ANC) less than 1,500 cells per microliter and is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (including both mature neutrophils and band forms).


- '''Severe Neutropenia (Agranulocytosis):''' ANC <500 cells/microliter
* '''Mild Neutropenia:''' ANC 1,000-1500 cells/microliter
* '''Moderate Neutropenia:''' ANC 500-1000 cells/microliter
* '''Severe Neutropenia ([[Agranulocytosis]]):''' ANC <500 cells/microliter


==Pathophysiology==
Neutropenia develops as a result of one of the three following mechanisms:


NOTE: These ranges are based on Caucasian patients, whereas African Americans and some ethnicities have mild neutropenia without increased risk of complications. Neutropenia in African American individuals is defined as an ANC < 1200 cells/microliter. This often overlooked fact results in overdiagnosis of neutropenia in African American population.[1]
# '''Impaired granulocyte production'''
#* [[Hematologic]] [[malignancy]] with bone marrow infiltration
#* Myelosuppressive [[chemotherapy]] or other medications that are toxic to the bone marrow
#* Nutritional deficiencies
# '''Margination:''' (process where free flowing blood cells exit circulation)
#* Splenic sequestration
#* Adherence to the vascular [[endothelium]]
# '''Peripheral destruction'''
#* Autoimmune [[hemolysis]]
#* Drug-induced [[hemolysis]]


Severe chronic neutropenia may be present at birth (congenital neutropenia) or may occur at any stage in life (acquired neutropenia). There are several types of severe chronic neutropenia:
==Causes==
The most common etiologies are constitutional or benign ethnic neutropenia (BEN) and drug-induced neutropenia. While the former is typically benign, as the title suggests, and not associated with significant complications, drug-induced neutropenia is often related to underlying cancer or medications that can suppress the bone marrow and can be severe and life-threatening if not identified and treated urgently.


'''Severe congenital neutropenia''' — a rare inherited form of the disease usually detected soon after birth. It affects children mainly and may result in premature loss of teeth and peremptory gum infections. The most severe form of chronic congenital neutropenia is known as Kostmann’s syndrome. It is genetically heterogeneous. Most commonly, it arises as a result of new,autosomal dominant mutations in the gene, ELA2, encoding the neutrophil granule protease, neutrophil elastase, NE. The gene responsible for many cases of autosomal recessively inherited severe congenital neutropenia is HAX1. The mechanism for congenital neutropenia is not well-understood. There is evidence that mutations in neutrophil elastase, or in other genes associated with syndromic forms of neutropenia, disrupt its intracellular trafficking. Apoptosis may be a final effector for neutropenia, but the original studies from Dale and Aprikian supporting this pathway were retracted.
==Epidemiology and Demographics==
 
Neutropenia is typically identified in at-risk patients undergoing [[cytotoxic]] [[chemotherapy]] or on other myelosuppressive medications. As noted above, some ethnicities have an unusually high prevalence of incidentally identified mild neutropenia, also termed constitutional or benign ethnic neutropenia (BEN). This is most common in blacks, Yemenites, West Indians, and Arab Jordanians and is suggested to be caused by a mutation in the [[Duffy antigen]] on red blood cells that helps to confer resistance to [[malaria]]. As the name suggests, these cases are typically mild and do not result in immunosuppression.
'''Cyclic neutropenia''' — tends to occur every three weeks and lasting three to six days at a time due to changing rates of cell production by the bone marrow. It is often present among several members of the same family. Cyclic neutropenia is also the result of autosomal dominantly inherited mutations in ELA2, the gene encoding neutrophil elastase.


'''Idiopathic neutropenia''' — a rare form of neutropenia which develops in children and adults usually in response to an illness. It is diagnosed when the disorder cannot be attributed to any other diseases and often causes life-threatening infections.
==Screening==
There are no routine screening recommendations for [[neutropenia]]. [[Neutropenia]] is typically identified incidentally on routine blood work or while monitoring after [[cytotoxic]] therapy.


'''Myelokathexis''' — a rare form of inherited autosomal dominant disease associated with severe neutropenia. Some but not all patients have warts, Hypogammaglobulinemia, and recurrent Infections. Therefore myelokathexis is also known as the W.H.I.M. syndrome. In spite of severe neutropenia (low number of neutrophils) in peripheral blood of myelokathexis patients, their bone marrow is hypercellular and it is packed with mature neutrophils indicating an impaired mobilization of hematopoietic cells in this disorder. Truncating mutations in the human cytokine receptor CXCR4 gene were identified in most of the families afflicted by myelokathexis. The molecular mechanism is not yet defined. Recent reports demonstrate that CXCR4 mutations appear to result in an increased sensitivity of bone marrow hematopoietic cells to its ligand, a stromal-derived growth factor SDF-1 that provides proliferative and survival signals.
==Natural History, Complications and Prognosis==
[[Neutropenia]] is a frequent finding on blood differential. When identified, attention must be placed on identifying underlying medication toxicities, [[autoimmune disorders]] or hematological malignancies, or various infections. While most patients with mild neutropenia recover quickly and without complications, severe medication-related neutropenia can be fatal in up to 10%.<ref name="PMID18043241">{{cite journal |author=Andrès E, Maloisel F. |title=Idiosyncratic drug-induced agranulocytosis or acute neutropenia. |journal=Curr Opin Hematol. |volume=15|issue=1 |pages=15-21 |year=2008|pmid=18043241 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/18043241}}</ref> Close attention must be given to identifying poor prognostic indicators, early signs of infection, and any cyclic pattern to this hematologic abnormality to avoid potentially fatal complications.


'''Autoimmune neutropenia''' — most common in infants and young children where the body identifies the neutrophils as enemies and makesantibody to destroy them. This form usually lessens in severity within two years of diagnosis.
[[Febrile neutropenia]] is an often fatal complication of severe neutropenia, with fever often being the only presenting symptom of an underlying infection.


'''Drug-induced neutropenia''' — Many drugs can cause agranulocytosis (complete absence of white cells) and neutropenia. Manyanti-neoplastic drugs cause agranulocytosis and neutropenia by bone marrow suppression. Neutropenia and agranulocytosis can also result from antibody or complement-mediated damage to the stem cells. Some drugs may cause increased peripheral destruction of white cells. About 75% of all cases of agranulocytosis in the United States are related to medication. Clozapine, File:Example.jpgprocainamide, anti-thyroid drugs (e.g. methimazole, and sulfasalazine are at the top of the list of drugs causing this problem, but many others (such as antiepileptics) have been implicated.
==Diagnosis==
In patients with severe [[neutropenia]], the neutrophil-mediated inflammatory process in the setting of infection is often blunted. Fever can be the sole presenting symptom. The risk of infection increases with the degree and duration of neutropenia with prolonged neutropenia defined as >7 days.


==Pathophysiology==
Neutropenia develops as a result of one of the three following mechanisms:


'''1) Impaired granulocyte production'''
Per 2002 IDSA <ref name="PMID21258094">{{cite journal |author=Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. |title=Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america|journal=Clin Infect Dis. |volume=52 |issue=4 |pages=e56-95 |year=2011 |pmid=21258094 |doi=|url=http://www.ncbi.nlm.nih.gov/pubmed/21258094}}</ref> and 2013 ASCO <ref name="PMID23319691">{{cite journal |author=Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, Kuderer NM, Langston AA, Marr KA, Rolston KV, Ramsey SD |title=Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline=J Clin Oncol. |volume=31 |issue=6 |pages=794-810 |year=2013 |pmid=23319691 |doi=|url=http://www.ncbi.nlm.nih.gov/pubmed/23319691}}</ref> guidelines, [[febrile neutropenia]] requires both of the following criteria:
#[[Fever]]: single oral temperature >38.3 C/101 F or sustained temperature >38 C/100.4 F for 1 hour.'''
#Severe neutropenia: ANC< 500 cells/microliter.'''


- Hematologic malignancy with bone marrow infiltration
===History and Symptoms===
[[Neutropenia]] can go undetected until the patient develops secondary, and often severe, [[infection]]s or [[sepsis]]. Some common infections can take an unexpected course in neutropenic patients; formation of [[pus]], for example, can be notably absent, as this requires circulating neutrophil granulocytes. 
History should focus on symptoms suggestive of malignancy or infections, patient or family history of autoimmune or [[immunodeficiency]] disorders, risk factors for infections including [[HIV]] and [[hepatitis]], and any unusual dietary practices or history of [[bariatric surgery]].  Medications should be reviewed with particular attention to chemotherapeutics, antibiotics, [[antiepileptics]], and psychoactive drugs as well as documenting any new medications started within the preceding few months.


- Myelosuppressive chemotherapy or other medications that are toxic to the bone marrow
Common presenting symptoms in neutropenic patients include:
*[[Fever]]
*Frequent [[infections]] due to lessened ability to fight [[bacterial]] infections
*Mouth [[ulcers]]
*[[Diarrhea]]
*[[Burning sensation when urinating]]
*Unusual redness, pain, or [[swelling]] around a wound
*[[Sore throat]]
*[[Shortness of breath]]
*Shaking [[chills]]


- Nutritional deficiencies
===Physical Examination===
Physical examination should focus on identifying any potential signs of [[infection]] and is directed by the patients' presenting symptoms.  A rectal examination should not be performed in a patient with [[neutropenia]].


===Laboratory Findings===
[[Neutropenia]] is detected on a full blood count. A peripheral [[blood smear]] is often useful to evaluate for abnormal morphology of the visible cells, which may help suggest the underlying cause. Additional laboratory studies include evaluation of metabolic abnormalities, genetic causes neutropenia, and toxic causes.


'''2) Margination''' (process where free flowing blood cells exit circulation)
===Imaging Findings===
[[Neutropenia]] is not identified on or correlated with any particular imaging. In the cases of [[neutropenic fever]], imaging findings are dependent upon the source of the [[fevers]]. Initial evaluation for neutropenic fever should include chest radiography to evaluate for pulmonary infiltrates or effusions.  Further imaging, such as CT or MRI scans, are indicated depending upon presenting symptoms and physical examination findings.


- Splenic sequestration
===Other Diagnostic Studies===
Other diagnostic studies for [[neutropenia]] include [[bone marrow biopsy]], which may be helpful when the etiology is uncertain, or serious causes such as [[malignancy]] and marrow replacement are suspected.


- Adherence to the vascular endothelium
==Treatment==
===Medical Therapy===
There is no specific therapy for [[neutropenia]] itself aside from removing the offending agents in drug-induced cases and treating the underlying disease in other, however recombinant [[Granulocyte-colony stimulating factor|G-CSF]] (granulocyte-colony stimulating factor) can be considered to speed myeloid reconstitution.


Asymptomatic, mild to moderate neutropenia can often be monitored closely on an outpatient basis with serial CBCs and evaluation for medications, infections, or alternative sources of neutropenia as described in detail above.  Offending medications are often held and the patient is monitored for response to discontinuation while evaluating for alternative, more concerning etiologies. With mild neutropenia, medications can often be reintroduced after neutrophil counts recover as the neutropenia is typically dose-dependent.


'''3) Peripheral destruction'''
Patients who are febrile, acutely ill, or with severe neutropenia often warrant urgent hospitalization for close monitoring and treatment.  Offending medications must be discontinued as drug-induced [[agranulocytosis]] presents up to a 10% mortality and is very likely to recur if the offending agent is restarted. 


- Autoimmune [[hemolysis]]
===Complications===
There are no intrinsic complications of [[neutropenia]], however people who are neutropenic are at risk for infections and [[febrile neutropenia]].


- Drug-induced [[hemolysis]]
====Febrile Neutropenia====
:'''Low risk patients:''' ANC>100 cells/microliter, normal liver and renal function, normal chest x-ray, no evidence of central line infection, MASCC >21, and duration of neutropenia expected <7 days in a patient with close monitoring and access to medical care.
::* [[Ciprofloxacin]] 500mg PO BID + amoxicillin/clavulanate 500mg PO TID


==Causes==
:'''High risk patients:''' Hospitalize and initiate empiric parenteral antimicrobial therapy. IDSA guidelines recommend initial monotherapy as below.
The most common etiologies are constitutional or benign ethnic neutropenia (BEN) and drug-induced neutropenia.
::* [[Cefepime]] 2 g IV Q8H
::* [[Meropenem]] 1 g IV Q8H
::* [[Imipenem]]/cilastatin 500 mg IV Q6H
::* [[Piperacillin]]/tazobactam 4.5 g IV Q6H
::* [[Ceftazidime]] 2 g IV Q8H (recent data shows increasing resistance to ceftazidime and inferior Gram-positive coverage to alternative regimens)


BEN is more often seen in blacks, Yemenites, West Indians, and Arab Jordanians with up to 4.5% prevalence in these populations <ref name="pmid17404350">{{cite journal |author=Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP |title=Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences |journal=Ann. Intern. Med. |volume=146 |issue=7 |pages=486-92 |year=2007 |pmid=17404350 |doi=|url=http://www.annals.org/cgi/content/abstract/146/7/486}}</ref>. In these individuals, a mutation in the Duffy antigen gene - a gene which encodes a red blood cell receptor used by [[malaria]] to enter these cells - both confers a protective effect against this parasite and, for unclear reasons, lowers the circulating neutrophil count. While quite common, the neutropenia is typically mild (ANC 1,000-1500 cells/microliter) and does not predispose to increased risk of infection or increased risk of febrile neutropenia in the setting of chemotherapy as these individuals have normal bone marrow neutrophil reserves
:'''Indications for resistant Gram-positive coverage:''' Vancomycin or linezolid is NOT recommended as part of initial treatment unless one of the following is present and, if started, should be discontinued after 2-3 days if there is no evidence of Gram-positive infection.
<ref name="PMID3181399">{{cite journal |author=Shoenfeld Y, Alkan ML, Asaly A, Carmeli Y, Katz M |title=Benign familial leukopenia and neutropenia in different ethnic groups |journal=Eur J Haematol. |volume=41 |issue=3 |pages=273-7 |year=1988 |pmid=3181399 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/3181399}}</ref>
::* Hemodynamic instability
<ref name="PMID4027348">{{cite journal |author=Shoenfeld Y, Ben-Tal O, Berliner S, Pinkhas J |title=The outcome of bacterial infection in subjects with benign familial leukopenia (BFL) |journal=Biomed Pharmacother. |volume=39 |issue=1 |pages=23-6 |year=1985 |pmid=4027348 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/4027348}}</ref>
::* Suspected catheter-associated infection
<ref name="PMID20194862">{{cite journal |author=Hsieh MM, Tisdale JF, Rodgers GP, Young NS, Trimble EL, Little RF |title=Neutrophil count in African Americans: lowering the target cutoff to initiate or resume chemotherapy? |journal=J Clin Oncol. |volume=28 |issue=10 |pages=1633-7 |year=2009 |pmid=20194862 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/20194862}}</ref>.
::* [[Mucositis]] or cellulitis
::* [[Pneumonia]]
::* History of [[MRSA]] infection or colonization
::* Gram-positive [[bacteremia]] prior to final culture results
::* Recent [[fluoroquinolone]] [[prophylaxis]]


Malignancy is often associated with neutropenia, due to impaired production from myelodysplastic syndromes and hematological malignancies with bone marrow infiltration, hemolysis and impaired production from cytotoxic chemotherapy, and antibody-mediated destruction of neutrophils.
:'''Persistent Fever:''' Continue empiric therapy until either culture data is available to direct management or after 3-5 days if the patient fails to improve. The median time to defercescence in adequately treated patients is 5 days with hematologic malignancies and 2-3 days with solid tumors. If the patient is still febrile or develops recurrent fevers after this time period further work up is suggested.
:# Re-evaluate sources of infection
:# Re-evaluate indications for resistant [[Gram-positive]] coverage and consider adding [[vancomycin]] or [[linezolid]].
:# Re-evaluate indications for resistant [[Gram-negative]] organisms and [[anaerobes]] and consider broadening to [[carbapenem]] antibiotics.
:# Consider [[fungal]] coverage in high risk patients if fevers persist after 4-7 days of appropriate antibiotic coverage and duration of neutropenia is expected to last >7 days. :Consider the following antifungals.
:#* [[Caspofungin]] 70 mg IV x 1 dose, then 50mg IV daily
:#* Liposomal [[Amphotericin]] B 3 mg/kg/day
:#* [[Voriconazole]] 6 mg/kg IV Q12H x 2 doses, then 4 mg/kg IV Q12H


Alternative etiologies include post-infectious neutropenia resulting from bacterial, fungal, or viral infections.  While bacterial infections typically cause leukocytosis, Salmonella and Shigella enteritis, brucellosis, tularemia, tuberculosis, and rickettsial diseases such as Rocky Mountain Spotted Fever (RMSF) can present with neutropenia. Parasitic diseases with neutropenia include Leishmaniasis with hemolysis and splenic sequestration and malaria due to hyper-reactive malarial splenomegaly (HMS). Viral etiologies include HIV, EBV, CMV, HHV-6, viral hepatitis, dengue, yellow fever, and common childhood exanthematous viruses including measles, varicella, and rubella where ANC nadirs around the time of the onset of rash.  
:::Caspofungin provides excellent coverage for [[Candida]] and is well tolerated, however nodular pulmonary infiltrates warrant coverage of [[Aspergillus]] with Voriconazole or Amphotericin B as [[echinocandins]] do not provide adequate coverage of Aspergillus or [[endemic]] fungi.


Immunodeficiencies are frequently associated with neutropenia (38% in Hyper IgM syndrome, 12% in CVID, and 7% in X-linked agammaglobulinemia) as are autoimmune disorders including up to 50% of patients with systemic lupus erythematosus, yet with lower overall prevalence. While rheumatoid arthritis infrequently presents with neutropenia, severe neutropenia can develop in the setting of large granular lymphocyte (LGL) leukemia or Felty syndrome <ref name="PMID6979979">{{cite journal |author=Bucknall RC, Davis P, Bacon PA, Jones JV |title=Neutropenia in rheumatoid arthritis: studies on possible contributing factors |journal=Ann Rheum Dis. |volume=41 |issue=3 |pages=242-7 |year=2009 |pmid=6979979 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed?term=6979979}}</ref>.
:'''Duration of Antimicrobials''' <br/>
::*Documented infection: Continue antimicrobials as directed by culture data. Continue treatment for the standard duration for that particular infection and until myeloid recovery (ANC>500 cells/microliter). If counts recover prior to completing the treatment course, consider transition to an oral regimen guided by culture data. <br/>
::*Negative Cultures: Continue empiric antimicrobial regimen until myeloid recovery (ANC>500 cells/microliter). If afebrile with no evidence of ongoing infection, consider transition to oral regimen (e.g. Ciprofloxacin + [[Amoxicillin]]/Clavulanate) and continue until myeloid recovery.


Finally, nutritional deficiencies resulting in neutropenia are typically attributed to vitamin B12, folate, and copper and are related to inadequate dietary intake, pernicious anemia, bariatric surgery, and malabsorptive syndromes.
===Surgery===
There are no surgical treatments for [[neutropenia]]. In patients' with [[neutropenic fever]], surgical intervention may be necessary depending on the sources of their infections.


===Life Threatening Causes===
===Primary Prevention===
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.
Prevention of neutropenia is dependent upon avoiding certain medications or treatment of underlying conditions.
 
=== Common Causes ===
* [[Aplastic anemia]]
* [[Cancer]]
* [[List of chemotherapeutic agents#Cytotoxic Chemotherapy|Cytotoxic chemotherapy]]
* [[Hemodialysis]]
* [[Medications]]
* [[Radiation therapy]]
* [[avitaminosis|Vitamin deficiencies e.g. folate, Vitamin B12]]
 
=== Causes by Organ System ===
 
{|style="width:80%; height:100px" border="1"
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Chemical / poisoning'''
|bgcolor="Beige"|[[Arsenic trioxide]], [[gold salts]], [[strontium|strontium-89]]
|-
|-bgcolor="LightSteelBlue"
| '''Dermatologic'''
|bgcolor="Beige"|[[Chediak-Higashi disease]], [[dyskeratosis congenita|dyskeratosis congenita, x-linked]], [[Elejalde syndrome ]], reticular dysgenesis, reticular dysplasia
|-
|-bgcolor="LightSteelBlue"
| '''Drug Side Effect'''
|bgcolor="Beige"| [[5-azacytidine]], [[acetophenazine]], [[aclarubicin]], [[actinomycin D]], [[acyclovir]], [[aflibercept]], [[albendazole]], [[alemtuzumab]], [[allopurinol]], [[amantadine]], [[amiloride]], [[aminoglutethimide]], [[aminoglutethimide]], [[aminopyrine]], [[amiodarone]],[[amodiaquine]], [[ampicillin]], [[amsacrine]], [[anakinra]], [[anidulafungin]], [[anti-thymocyte globulin]], [[antibiotics]], [[antipyrine]], [[aprepitant]], [[aripiprazole]], [[arsenic trioxide]], [[asenapine]], [[atazanavir]], [[atovaquone]], [[auranofin]], [[azacitidine]], [[azathioprine]], [[aztreonam]], [[barbiturates]], [[belinostat]], [[benazepril]], [[bendamustine]], [[bevacizumab]], [[blinatumomab]], [[boceprevir]], [[bortezomib]], [[bosutinib]], [[brentuximab]], [[busulfan]], [[cabazitaxel]], [[cabozantinib]], [[canakinumab]], [[candesartan]], [[capecitabine]], [[captopril]], [[carbimazole]], [[carboplatin]], [[carfilzomib]], [[carmustine]], [[cefaclor]], [[cefadroxil]], [[cefazolin]], [[cefepime]], [[cefixime]], [[cefoperazone]], [[cefotetan]], [[cefotiam]], [[cefoxitin]], [[ceftaroline]], [[ceftriaxone]], [[cefuroxime]], [[cephalexin]], [[cephapirin]], [[cephradine]], [[cetuximab]], [[chemotherapy]], [[chlorambucil]], [[chloramphenicol]], [[chloroquine]], [[chlorpromazine]], [[chlorthalidone]], [[cidofovir]], [[cilazapril]], [[cimetidine]], [[cisplatin]], [[cladribine]], [[clarithromycin]], [[clindamycin]], [[clofarabine]], [[clopidogrel]], [[clozapine]], [[colchicine]], [[crizotinib]], [[cromolyn]], [[cyclophosphamide]], [[cytarabine]], [[cytosine arabinoside]], [[dabrafenib]],[[dacarbazine]], [[daclatasvir]], [[dactinomycin]], [[dasatinib]], [[daunorubicin]], [[decitabine]], [[deferasirox]], [[deferiprone]], [[delavirdine]], [[desipramine]], [[dexrazoxane]], [[diatrizoate]], [[diazepam]], [[diazoxide]],  [[dicloxacillin]], [[Diethylpropion]][[diflunisal]], [[dipyrone]], [[docetaxel]], [[dolutegravir]], [[doripenem]], [[dothiepin]], [[doxorubicin]], [[doxycycline]],  [[efavirenz]], [[eflornithine]], [[elvitegravir]], [[enalapril]], [[enalaprilat]], [[enfuvirtide]], [[enzalutamide]], [[epirubicin]], [[eprosartan]], [[eribulin]], [[etanercept]], [[ethacrynic acid]], [[ethambutol]], [[ethosuximide]], [[ethotoin]], [[etodolac]], [[etoposide]], [[everolimus]], [[felbamate]], [[fentanyl]],  [[fidaxomicin]], [[flucytosine]], [[fludarabine]], [[fluorouracil]], [[fluoxetine]], [[fosamprenavir]], [[foscarnet]], [[fosinopril]], [[ganciclovir]], [[gefitinib]], [[gemcitabine]], [[gemifloxacin mesylate]], [[glyburide]], [[golimumab]], [[griseofulvin]], [[guanidinium]], [[haloperidol]], [[hydroxycarbamide]], [[hydroxyurea]], [[ibuprofen lysine]], [[ibritumomab tiuxetan]], [[ibrutinib]], [[ibuprofen]], [[idarubicin]], [[idelalisib]], [[iloperidone]], [[imatinib]], [[imipenem cilastatin]], [[indinavir]], [[indomethacin]], [[infliximab]], [[interferon alfa-2a]], [[interferon alfa-2b]], [[interferon alfacon-1]], [[interferon beta-1b]], [[irinotecan]], [[isoniazid]], [[isotretinoin]], [[itraconazole]], [[ixabepilone]], [[lamivudine]], [[lamotrigine]], [[lansoprazole]], [[lenalidomide]], [[levamisole]], [[levetiracetam]], [[levomepromazine]], [[lincomycin]], [[linezolid]], [[lisinopril]], [[loxapine]], [[lurasidone]], [[maprotiline]], [[maraviroc]], [[meclofenamate]], [[mercaptopurine]], [[meropenem]], [[mesalamine]], [[methazolamide]], [[methimazole]], [[methotrexate]], [[methyldopa]], [[metolazone]], [[mexiletine]], [[mianserin]], [[micafungin]], [[mifamurtide]], [[milnacipran]], [[minocycline]], [[mirtazapine]], [[mitotane]], [[mitoxantrone]], [[moexipril]], [[moxalactam]], [[mycophenolate]], [[mycophenolic acid]], [[nafcillin]], [[naproxen]], [[nefazodone]], [[nelarabine]], [[nelfinavir]], [[nevirapine]], [[nilotinib]], [[nilutamide]], [[norfloxacin]], [[nortriptyline]], [[obinutuzumab]], [[ofatumumab]], [[ofloxacin]], [[olanzapine]], [[olaparib]], [[olsalazine]],[[omacetaxine]], [[omeprazole]], [[oprelvekin]], [[oxacillin]], [[oxaliplatin]], [[paclitaxel]], [[palbociclib]], [[paliperidone]], [[panobinostat]], [[pantoprazole]], [[pazopanib]], [[peginterferon alfa-2a]], [[peginterferon alfa-2b]], [[pemetrexed]], [[penicillamine]], [[penicillin]], [[penicillin G]], [[pentamidine]], [[pentostatin]], [[peramivir]], [[perazine]], [[perindopril]], [[pertuzumab]], [[phenylbutazone]], [[phenytoin]],  [[piperacillin]], [[piperaquine]], [[pipothiazine]], [[piroxicam]], [[pixantrone]], [[pomalidomide]],  [[ponatinib]], [[posaconazole]], [[pralatrexate]], [[prednisone]], [[probenecid]], [[procainamide]], [[procarbazine]], [[prochlorperazine]], [[proguanil]], [[propylthiouracil]], [[pyrimethamine]], [[quetiapine]], [[quinapril]], [[quinidine]], [[quinine]], [[radium chloride]], [[raltitrexed]], [[ramipril]], [[ramucirumab]], [[ranitidine]], [[rasagiline]], [[rasburicase]], [[regorafenib]], [[remoxipride]], [[ribavirin]], [[rifabutin]], [[rifapentine]], [[rifaximin]], [[rilonacept]], [[riluzole]], [[risperidone]], [[ritodrine]], [[ritonavir]], [[rituximab]], [[romidepsin]], [[ruxolitinib]], [[saquinavir]], [[satraplatin]], [[secukinumab]], [[sirolimus]], [[sodium aurothiomalate]], [[sofosbuvir]], [[sorafenib]], [[stavudine]], [[stiripentol]], [[succimer]], [[Sulfacetamide]], [[Sulfamethoxazole/Trimethoprim (oral)]],
[[sulfasalazine]], [[sulfonamide]], [[sulindac]], [[sunitinib]], [[suramin]], [[tacrolimus]], [[tedizolid]], [[teicoplanin]], [[temozolomide]], [[temsirolimus]], [[teniposide]], [[tenofovir]], [[terbinafine]], [[teriflunomide]], [[thalidomide]], [[thiothixene]], [[ticarcillin]], [[ticlopidine]], [[tipranavir]], [[tocilizumab]], [[tofacitinib]], [[tolazamide]], [[tolmetin]], [[topotecan]], [[tositumomab]], [[trabectedin]], [[trametinib]], [[trandolapril]], [[trastuzumab]], [[trimethadione]], [[trimethoprim]], [[trimetrexate]], [[valganciclovir]], [[valproic acid]], [[valrubicin]], [[valsartan]], [[vancomycin]], [[vandetanib]], [[vesnarinone]], [[vincristine]], [[vindesine]], [[vinflunine]], [[vinorelbine]], [[zidovudine]], [[zileuton]], [[ziprasidone]], [[ziv-aflibercept]], [[zoledronic acid]]
|-
|-bgcolor="LightSteelBlue"
| '''Ear Nose Throat'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Endocrine'''
|bgcolor="Beige"|[[Hyperthyroidism]]
|-
|-bgcolor="LightSteelBlue"
| '''Environmental'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Gastroenterologic'''
|bgcolor="Beige"|[[Glycogen storage disorder]], [[hypersplenism]], [[Shwachman-Diamond syndrome]]
|-
|-bgcolor="LightSteelBlue"
| '''Genetic'''
|bgcolor="Beige"|[[Barth syndrome]], [[cartilage-hair hypoplasia]], [[Chediak-Higashi disease]], [[Cohen syndrome]], [[Dubowitz syndrome]], [[Elejalde syndrome ]], [[familial histiocytic reticulosis]], [[Fanconi syndrome]], [[fumarate hydratase deficiency]], [[Griscelli syndrome|Griscelli syndrome type 1]], [[methylmalonic aciduria]], [[myelokathexis]], [[propionic acidemia]], [[propionyl-CoA carboxylase|propionyl-CoA carboxylase deficiency PCCA type]], [[Shwachman-Diamond syndrome]], [[WHIM syndrome]]
|-
|-bgcolor="LightSteelBlue"
| '''Hematologic'''
|bgcolor="Beige"|Alloimmune neonatal neutropenia, alloimmune neutropenia in infancy, [[aplastic anemia]], [[neutropenia|autoimmune neutropenia]], [[chronic lymphocytic leukemia]], [[cyclical neutropenia]], [[familial histiocytic reticulosis]], [[Hermansky-Pudlak syndrome]], [[histiocytosis X]], [[hypersplenism]], [[Kostmann disease]], [[myelodysplastic syndrome]], [[myelofibrosis]], [[pancytopenia]], [[paroxysmal nocturnal haemoglobinuria]], [[Shwachman-Diamond syndrome]], [[x-linked agammaglobulinemia]]
|-
|-bgcolor="LightSteelBlue"
| '''Iatrogenic'''
|bgcolor="Beige"| [[Hemodialysis]], [[radiation therapy]]
|-
|-bgcolor="LightSteelBlue"
| '''Infectious Disease'''
|bgcolor="Beige"|[[Brucellosis]], [[cytomegalovirus]], [[dengue]], [[Epstein-Barr virus]], [[hepatitis A]], [[hepatitis B]], [[hepatitis C]], [[hepatitis]], [[human granulocytic ehrlichiosis]], [[human immunodeficiency virus]], [[ehrlichiosis|human monocytotropic ehrlichiosis]], [[kala azar]], [[Kostmann disease]], [[lassa fever]], [[Lyme disease]], [[malaria]], [[measles]], [[rickettsiae]], [[rickettsial infections]], [[rocky mountain spotted fever]], [[rubella]], [[salmonella infection]], [[sepsis]], [[severe acute respiratory syndrome]], [[shigellosis]], [[tuberculosis]], [[tularemia]], [[varicella]], [[visceral leishmaniasis]], [[WHIM syndrome]]
|-
|-bgcolor="LightSteelBlue"
| '''Musculoskeletal / Ortho'''
|bgcolor="Beige"|[[Cartilage-hair hypoplasia]], [[metaphyseal chondrodysplasia, Mckusick type]]
|-
|-bgcolor="LightSteelBlue"
| '''Neurologic'''
|bgcolor="Beige"|[[Fumarate hydratase deficiency]]
|-
|-bgcolor="LightSteelBlue"
| '''Nutritional / Metabolic'''
|bgcolor="Beige"|[[Copper deficiency]], [[glutathione synthase|glutathione synthase deficiency]], [[glycogen storage disorder]], [[glycogen storage disease type I|glycogenosis type 1b]], [[orotic aciduria|hereditary orotic aciduria]], [[isovaleric acidemia]], [[methylmalonic aciduria]], [[propionic acidemia]], [[propionyl-CoA carboxylase|propionyl-CoA carboxylase deficiency PCCA type]], [[vitamin deficiencies]]
|-
|-bgcolor="LightSteelBlue"
| '''Obstetric/Gynecologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Oncologic'''
|bgcolor="Beige"|[[Chronic lymphocytic leukemia]], [[hairy cell leukemia]], [[histiocytosis X]], [[leukemia]], [[myelodysplastic syndrome]], [[myelofibrosis]]
|-
|-bgcolor="LightSteelBlue"
| '''Opthalmologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Overdose / Toxicity'''
|bgcolor="Beige"|[[Alcoholism]]
|-
|-bgcolor="LightSteelBlue"
| '''Psychiatric'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Pulmonary'''
|bgcolor="Beige"|[[Severe acute respiratory syndrome]]
|-
|-bgcolor="LightSteelBlue"
| '''Renal / Electrolyte'''
|bgcolor="Beige"|[[Fanconi syndrome]]
|-
|-bgcolor="LightSteelBlue"
| '''Rheum / Immune / Allergy'''
|bgcolor="Beige"| Alloimmune neonatal neutropenia, alloimmune neutropenia in infancy, [[autoimmune lymphoproliferative syndrome type 1]], [[autoimmune lymphoproliferative syndrome type 2]], [[neutropenia|autoimmune neutropenia]], [[common variable immune deficiency]], [[Felty's syndrome]], [[histiocytosis X]], [[hyper-immunoglobulin M syndrome]], [[lupus]], [[rheumatoid arthritis]], [[neutropenia|secondary autoimmune neutropenia]], [[WHIM syndrome]], [[x-linked agammaglobulinemia]], [[x-linked hyperimmunoglobulin M syndrome]]
|-
|-bgcolor="LightSteelBlue"
| '''Sexual'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Trauma'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Urologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Dental'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Miscellaneous'''
|bgcolor="Beige"| No underlying causes
|-
|}
 
=== Causes in Alphabetical Order ===
{{columns-list|3|
* [[5-azacytidine]]
* [[Acetophenazine]]
* [[Aclarubicin]]
* [[Actinomycin D]]
* [[Acyclovir]]
* [[Aflibercept]]
* [[Albendazole]]
* [[Alcoholism]]
* [[Alemtuzumab]]
* Alloimmune neonatal neutropenia
* Alloimmune neutropenia in infancy
* [[Allopurinol]]
* [[Amantadine]]
* [[Amiloride]]
* [[Aminoglutethimide]]
* [[Aminopyrine]]
* [[Amiodarone]]
* [[Amitriptyline]]
* [[Amodiaquine]]
* [[Ampicillin]]
* [[Amsacrine]]
* [[Anakinra]]
* [[Anidulafungin]]
* [[Antibiotics]]
* [[Antipyrine]]
* [[Anti-thymocyte globulin]]
* [[Aplastic anemia]]
* [[Aprepitant]]
* [[Aripiprazole]]
* [[Arsenic trioxide]]
* [[Asenapine]]
* [[Atazanavir]]
* [[Atovaquone]]
* [[Auranofin]]
* [[Autoimmune lymphoproliferative syndrome type 1]]
* [[Autoimmune lymphoproliferative syndrome type 2]]
* [[neutropenia|Autoimmune neutropenia]]
* [[Azacitidine]]
* [[Azathioprine]]
* [[Aztreonam]]
* [[Barbiturates]]
* [[Barth syndrome]]
* [[Belinostat]]
* [[Benazepril]]
* [[Bendamustine]]
* [[Bevacizumab]]
* [[Blinatumomab]]
* [[Boceprevir]]
* [[Bortezomib]]
* [[Bosutinib]]
* [[Brentuximab vedotin]]
* [[Brucellosis]]
* [[Busulfan]]
* [[Cabazitaxel]]
* [[Cabozantinib]]
* [[Canakinumab]]
* [[Candesartan]]
* [[Capecitabine]]
* [[Captopril]]
* [[Carbimazole]]
* [[Carboplatin]]
* [[Carfilzomib]]
* [[Carmustine]]
* [[Cartilage-hair hypoplasia]]
* [[Caspofungin]]
* [[Cefaclor]]
* [[Cefadroxil]]
* [[Cefazolin]]
* [[Cefepime]]
* [[Cefixime]]
* [[Cefoperazone]]
* [[Cefotetan]]
* [[Cefotiam]]
* [[Cefoxitin]]
* [[Ceftaroline]]
* [[Ceftriaxone]]
* [[Cefuroxime]]
* [[Cephalexin]]
* [[Cephapirin]]
* [[Cephradine]]
* [[Cetuximab]]
* [[Chediak-Higashi disease]]
* [[Chemotherapy]]
* [[Chlorambucil]]
* [[Chloroquine]]
* [[Chlorpromazine]]
* [[Chlorthalidone]]
* [[Chronic lymphocytic leukemia]]
* [[Cidofovir]]
* [[Cilazapril]]
* [[Cimetidine]]
* [[Cisplatin]]
* [[Cladribine]]
* [[Clarithromycin]]
* [[Clindamycin]]
* [[Clofarabine]]
* [[Clofarabine]]
* [[Clopidogrel]]
* [[Clozapine]]
* [[Cohen syndrome]]
* [[Colchicine]]
* [[Common variable immune deficiency]]
* [[Copper deficiency]]
* [[Crizotinib]]
* [[Cyclical neutropenia]]
* [[Cyclophosphamide]]
* [[Cytarabine]]
* [[Cytomegalovirus]]
* [[Cytosine arabinoside]]
* [[Dabrafenib]]
* [[Dacarbazine]]
* [[Daclatasvir]]
* [[Dactinomycin]]
* [[Dasatinib]]
* [[Daunorubicin]]
* [[Decitabine]]
* [[Deferasirox]]
* [[Deferiprone]]
* [[Delavirdine]]
* [[Dengue]]
* [[Desipramine]]
* [[Dexrazoxane]]
* [[Diatrizoate]]
* [[Diazepam]]
* [[Diazoxide]]
* [[Dicloxacillin]]
* [[Diflunisal]]
* [[Dipyrone]]
* [[Docetaxel]]
* [[Dolutegravir]]
* [[Doripenem]]
* [[Dothiepin]]
* [[Doxorubicin]]
* [[Doxycycline]]
* [[Dubowitz syndrome]]
* [[dyskeratosis congenita|Dyskeratosis congenita, X-linked]]
* [[Efavirenz]]
* [[Eflornithine]]
* [[Elejalde syndrome]]
* [[Elvitegravir]]
* [[Enalapril]]
* [[Enalaprilat]]
* [[Enfuvirtide]]
* [[Enzalutamide]]
* [[Epirubicin]]
* [[Eprosartan]]
* [[Epstein-Barr virus]]
* [[Eribulin]]
* [[Etanercept]]
* [[Ethacrynic acid]]
* [[Ethambutol]]
* [[Ethosuximide]]
* [[Ethotoin]]
* [[Etodolac]]
* [[Etoposide]]
* [[Everolimus]]
* [[Familial histiocytic reticulosis]]
* [[Fanconi syndrome]]
* [[Felty's syndrome]]
* [[Fentanyl]]
* [[Fidaxomicin]]
* [[Flucytosine]]
* [[Fludarabine]]
* [[Fluorouracil]]
* [[Fluoxetine]]
* [[Fosamprenavir]]
* [[Foscarnet]]
* [[Fosinopril]]
* [[Fumarate hydratase deficiency]]
* [[Ganciclovir]]
* [[Gefitinib]]
* [[Gemcitabine]]
* [[Gemtuzumab ozogamicin]]
* [[glutathione synthase|Glutathione synthase deficiency]]
* [[Glyburide]]
* [[Glycogen storage disorder]]
* [[glycogen storage disease type I|Glycogenosis type 1b]]
* [[Gold salts]]
* [[Golimumab]]
* [[Griscelli syndrome|Griscelli syndrome type 1]]
* [[Griseofulvin]]
* [[Guanidinium]]
* [[Hairy cell leukemia]]
* [[Haloperidol]]
* [[Hemodialysis]]
* [[Hepatitis]]
* [[Hepatitis A]]
* [[Hepatitis B]]
* [[Hepatitis C]]
* [[orotic aciduria|Hereditary orotic aciduria]]
* [[Hermansky-Pudlak syndrome]]
* [[Histiocytosis X]]
* [[Human granulocytic ehrlichiosis]]
* [[Human immunodeficiency virus]]
* [[ehrlichiosis|Human monocytotropic ehrlichiosis]]
* [[Hydroxycarbamide]]
* [[Hydroxyurea]]
* [[Hyper-immunoglobulin M syndrome]]
* [[Hypersplenism]]
* [[Hyperthyroidism]]
* [[Ibritumomab]]
* [[Ibrutinib]]
* [[Ibuprofen]]
* [[Ibuprofen lysine]]
* [[Idarubicin]]
* [[Idelalisib]]
* [[Iloperidone]]
* [[Imatinib]]
* [[Imipenem cilastatin]]
* [[Indinavir]]
* [[Indomethacin]]
* [[Infliximab]]
* [[Interferon alfa-2a]]
* [[Interferon alfa-2b]]
* [[Interferon alfacon-1]]
* [[Interferon beta-1b]]
* [[Irinotecan]]
* [[Isoniazid]]
* [[Isotretinoin]]
* [[Isovaleric acidemia]]
* [[Itraconazole]]
* [[Ixabepilone]]
* [[Kala azar]]
* [[Kostmann disease]]
* [[Lamivudine]]
* [[Lamotrigine]]
* [[Lansoprazole]]
* [[Lassa fever]]
* [[Lenalidomide]]
* [[Leukemia]]
* [[Levamisole]]
* [[Levetiracetam]]
* [[Levomepromazine]]
* [[Lincomycin]]
* [[Linezolid]]
* [[Lisinopril]]
* [[Loxapine]]
* [[Lupus]]
* [[Lurasidone]]
* [[Lyme disease]]
* [[Malaria]]
* [[Maprotiline]]
* [[Maraviroc]]
* [[Measles]]
* [[Meclofenamate]]
* [[Mercaptopurine]]
* [[Meropenem]]
* [[Mesalamine]]
* [[Metaphyseal chondrodysplasia, Mckusick type]]
* [[Methazolamide]]
* [[Methimazole]]
* [[Methotrexate]]
* [[Methyldopa]]
* [[Methylmalonic aciduria]]
* [[Metolazone]]
* [[Mexiletine]]
* [[Mianserin]]
* [[Micafungin]]
* [[Mifamurtide]]
* [[Milnacipran hydrochloride|Milnacipran]]
* [[Minocycline]]
* [[Mirtazapine]]
* [[Mitotane]]
* [[Mitoxantrone]]
* [[Moexipril]]
* [[Moxalactam]]
* [[Mycophenolate]]
* [[Mycophenolic acid]]
* [[Myelodysplastic syndrome]]
* [[Myelofibrosis]]
* [[Myelokathexis]]
* [[Nafcillin]]
* [[Naproxen]]
* [[Nefazodone]]
* [[Nelarabine]]
* [[Nelfinavir]]
* [[Nevirapine]]
* [[Nilotinib]]
* [[Nilutamide]]
* [[Norfloxacin]]
* [[Nortriptyline]]
* [[Obinutuzumab]]
* [[Ofatumumab]]
* [[Ofloxacin]]
* [[Olanzapine]]
* [[Olaparib]]
* [[Olsalazine]]
* [[Omacetaxine]]
* [[Omeprazole]]
* [[Oprelvekin]]
* [[Oxacillin]]
* [[Oxaliplatin]]
* [[Paclitaxel]]
* [[Palbociclib]]
* [[Paliperidone]]
* [[Pancytopenia]]
* [[Panobinostat]]
* [[Pantoprazole]]
* [[Paroxysmal nocturnal haemoglobinuria]]
* [[Pazopanib]]
* [[Peginterferon alfa-2a]]
* [[Peginterferon alfa-2b]]
* [[Pemetrexed]]
* [[Penicillamine]]
* [[Penicillin]]
* [[Penicillin G]]
* [[Pentamidine]]
* [[Pentostatin]]
* [[Peramivir]]
* [[Perazine]]
* [[Perindopril]]
* [[Pertuzumab]]
* [[Phenylbutazone]]
* [[Phenytoin]]
* [[Piperacillin]]
* [[Piperaquine]]
* [[Pipothiazine]]
* [[Piroxicam]]
* [[Pixantrone]]
* [[Pomalidomide]]
* [[Ponatinib]]
* [[Posaconazole]]
* [[Pralatrexate]]
* [[Prednisone]]
* [[Probenecid]]
* [[Procainamide]]
* [[Procarbazine]]
* [[Prochlorperazine]]
* [[Proguanil]]
* [[Propionic acidemia]]
* [[propionyl-CoA carboxylase deficiency|Propionyl-CoA carboxylase deficiency PCCA type]]
* [[Propylthiouracil]]
* [[Pyrimethamine]]
* [[Quetiapine]]
* [[Quinapril]]
* [[Quinidine]]
* [[Quinine]]
* [[Radiation therapy]]
* [[Radium chloride]]
* [[Raltitrexed]]
* [[Ramipril]]
* [[Ramucirumab]]
* [[Ranitidine]]
* [[Rasagiline]]
* [[Rasburicase]]
* [[Regorafenib]]
* [[Remoxipride]]
* [[Reticular dysgenesis]]
* [[Reticular dysplasia]]
* [[Rheumatoid arthritis]]
* [[Ribavirin]]
* [[Rickettsiae]]
* [[Rickettsial infections]]
* [[Rifabutin]]
* [[Rifapentine]]
* [[Rifaximin]]
* [[Rilonacept]]
* [[Riluzole]]
* [[Risperidone]]
* [[Ritodrine]]
* [[Ritonavir]]
* [[Rituximab]]
* [[Rocky mountain spotted fever]]
* [[Romidepsin]]
* [[Rubella]]
* [[Ruxolitinib]]
* [[Salmonella infection]]
* [[Saquinavir]]
* [[Satraplatin]]
* [[neutropenia|Secondary autoimmune neutropenia]]
* [[Secukinumab]]
* [[Sepsis]]
* [[Severe acute respiratory syndrome]]
* [[Shigellosis]]
* [[Shwachman-Diamond syndrome]]
* [[Sirolimus]]
* [[Sodium aurothiomalate]]
* [[Sofosbuvir]]
* [[Sorafenib]]
* [[Stavudine]]
* [[Stiripentol]]
* [[Strontium-89]]
* [[Succimer]]
* [[Sulfasalazine]]
* [[Sulfonamide]]
* [[Sulindac]]
* [[Sunitinib]]
* [[Suramin]]
* [[Tacrolimus]]
* [[Tedizolid]]
* [[Teicoplanin]]
* [[Temozolomide]]
* [[Temsirolimus]]
* [[Teniposide]]
* [[Tenofovir]]
* [[Terbinafine]]
* [[Teriflunomide]]
* [[Thalidomide]]
* [[Thiothixene]]
* [[Ticarcillin]]
* [[Ticlopidine]]
* [[Tipranavir]]
* [[Tocilizumab]]
* [[Tofacitinib]]
* [[Tolazamide]]
* [[Tolmetin]]
* [[Topotecan]]
* [[Tositumomab]]
* [[Trabectedin]]
* [[Trametinib]]
* [[Trandolapril]]
* [[Trastuzumab]]
* [[Trimethadione]]
* [[Trimethoprim]]
* [[Trimetrexate]]
* [[Tuberculosis]]
* [[Tularemia]]
* [[Valganciclovir]]
* [[Valproic acid]]
* [[Valrubicin]]
* [[Valsartan]]
* [[Vancomycin]]
* [[Vandetanib]]
* [[Varicella]]
* [[Vesnarinone]]
* [[Vincristine]]
* [[Vindesine]]
* [[Vinflunine]]
* [[Vinorelbine]]
* [[Visceral leishmaniasis]]
* [[Vitamin deficiencies]]
* [[WHIM syndrome]]
* [[X-linked agammaglobulinemia]]
* [[X-linked hyperimmunoglobulin M syndrome]]
* [[Zidovudine]]
* [[Zileuton]]
* [[Ziprasidone]]
* [[ziv-aflibercept]]
* [[Zoledronic acid]]
}}
 
 
==Epidemiology and Demographics==
Neutropenia is typically identified in at-risk patients undergoing cytotoxic chemotherapy or on other myelosuppressive medications. As noted above, some ethnicities have an unusually high prevalence of incidentally identified mild neutropenia, also termed constitutional or benign ethnic neutropenia (BEN).  This is most common in blacks, Yemenites, West Indians, and Arab Jordanians and is suggested to be caused by a mutation in the Duffy antigen on red blood cells that helps to confer resistance to malaria.  As the name suggests, these cases are typically mild and do not result in immunosuppression.


===Secondary Prevention===
Secondary prevention of neutropenia relies on careful avoidance of triggers, such as certain medications, or treatment of underlying conditions. Further discussion of the causes of neutropenia are reviewed above.


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
 
[[Category:Dermatology]]
[[Category:Disease]]
[[Category:Hematology]]
[[Category:Hematology]]
 
[[Category:Hepatology]]
{{WS}}
{{WH}}
{{WH}}
{{WS}}

Latest revision as of 23:39, 16 November 2016

Neutropenia Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

Overview

Neutropenia is a hematological disorder characterized by an abnormally low number of neutrophil granulocytes (a type of white blood cell). Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against infections by destroying bacteria in the blood. Hence, patients with neutropenia are more susceptible to bacterial infections and without prompt medical attention, the condition may become life-threatening. Neutropenia can be acute or chronic depending on the duration of the illness. A patient has chronic neutropenia if the condition lasts for greater than 3 months. It is sometimes used interchangeably with the term leukopenia. However, neutropenia is more properly considered a subset of leukopenia as a whole. Some patients, such as those with constitutional/benign ethnic neutropenia, suffer relatively few complications, however neutropenia related to cytotoxic chemotherapy, hematopoietic stem cell transplant, or other causes of bone marrow suppression may present as a medical emergency.

Historical Perspective

Neutropenia was first noted around the start of the 20th century on review of blood cell differentials described in patients with lupus, other autoimmune disorders, and with various drug toxicities.[1]

Classification

Calculated based on blood count differential, neutropenia is defined as an absolute neutrophil count (ANC) less than 1,500 cells per microliter and is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (including both mature neutrophils and band forms).

  • Mild Neutropenia: ANC 1,000-1500 cells/microliter
  • Moderate Neutropenia: ANC 500-1000 cells/microliter
  • Severe Neutropenia (Agranulocytosis): ANC <500 cells/microliter

Pathophysiology

Neutropenia develops as a result of one of the three following mechanisms:

  1. Impaired granulocyte production
  2. Margination: (process where free flowing blood cells exit circulation)
    • Splenic sequestration
    • Adherence to the vascular endothelium
  3. Peripheral destruction

Causes

The most common etiologies are constitutional or benign ethnic neutropenia (BEN) and drug-induced neutropenia. While the former is typically benign, as the title suggests, and not associated with significant complications, drug-induced neutropenia is often related to underlying cancer or medications that can suppress the bone marrow and can be severe and life-threatening if not identified and treated urgently.

Epidemiology and Demographics

Neutropenia is typically identified in at-risk patients undergoing cytotoxic chemotherapy or on other myelosuppressive medications. As noted above, some ethnicities have an unusually high prevalence of incidentally identified mild neutropenia, also termed constitutional or benign ethnic neutropenia (BEN). This is most common in blacks, Yemenites, West Indians, and Arab Jordanians and is suggested to be caused by a mutation in the Duffy antigen on red blood cells that helps to confer resistance to malaria. As the name suggests, these cases are typically mild and do not result in immunosuppression.

Screening

There are no routine screening recommendations for neutropenia. Neutropenia is typically identified incidentally on routine blood work or while monitoring after cytotoxic therapy.

Natural History, Complications and Prognosis

Neutropenia is a frequent finding on blood differential. When identified, attention must be placed on identifying underlying medication toxicities, autoimmune disorders or hematological malignancies, or various infections. While most patients with mild neutropenia recover quickly and without complications, severe medication-related neutropenia can be fatal in up to 10%.[2] Close attention must be given to identifying poor prognostic indicators, early signs of infection, and any cyclic pattern to this hematologic abnormality to avoid potentially fatal complications.

Febrile neutropenia is an often fatal complication of severe neutropenia, with fever often being the only presenting symptom of an underlying infection.

Diagnosis

In patients with severe neutropenia, the neutrophil-mediated inflammatory process in the setting of infection is often blunted. Fever can be the sole presenting symptom. The risk of infection increases with the degree and duration of neutropenia with prolonged neutropenia defined as >7 days.


Per 2002 IDSA [3] and 2013 ASCO [4] guidelines, febrile neutropenia requires both of the following criteria:

  1. Fever: single oral temperature >38.3 C/101 F or sustained temperature >38 C/100.4 F for 1 hour.
  2. Severe neutropenia: ANC< 500 cells/microliter.

History and Symptoms

Neutropenia can go undetected until the patient develops secondary, and often severe, infections or sepsis. Some common infections can take an unexpected course in neutropenic patients; formation of pus, for example, can be notably absent, as this requires circulating neutrophil granulocytes. History should focus on symptoms suggestive of malignancy or infections, patient or family history of autoimmune or immunodeficiency disorders, risk factors for infections including HIV and hepatitis, and any unusual dietary practices or history of bariatric surgery. Medications should be reviewed with particular attention to chemotherapeutics, antibiotics, antiepileptics, and psychoactive drugs as well as documenting any new medications started within the preceding few months.

Common presenting symptoms in neutropenic patients include:

Physical Examination

Physical examination should focus on identifying any potential signs of infection and is directed by the patients' presenting symptoms. A rectal examination should not be performed in a patient with neutropenia.

Laboratory Findings

Neutropenia is detected on a full blood count. A peripheral blood smear is often useful to evaluate for abnormal morphology of the visible cells, which may help suggest the underlying cause. Additional laboratory studies include evaluation of metabolic abnormalities, genetic causes neutropenia, and toxic causes.

Imaging Findings

Neutropenia is not identified on or correlated with any particular imaging. In the cases of neutropenic fever, imaging findings are dependent upon the source of the fevers. Initial evaluation for neutropenic fever should include chest radiography to evaluate for pulmonary infiltrates or effusions. Further imaging, such as CT or MRI scans, are indicated depending upon presenting symptoms and physical examination findings.

Other Diagnostic Studies

Other diagnostic studies for neutropenia include bone marrow biopsy, which may be helpful when the etiology is uncertain, or serious causes such as malignancy and marrow replacement are suspected.

Treatment

Medical Therapy

There is no specific therapy for neutropenia itself aside from removing the offending agents in drug-induced cases and treating the underlying disease in other, however recombinant G-CSF (granulocyte-colony stimulating factor) can be considered to speed myeloid reconstitution.

Asymptomatic, mild to moderate neutropenia can often be monitored closely on an outpatient basis with serial CBCs and evaluation for medications, infections, or alternative sources of neutropenia as described in detail above. Offending medications are often held and the patient is monitored for response to discontinuation while evaluating for alternative, more concerning etiologies. With mild neutropenia, medications can often be reintroduced after neutrophil counts recover as the neutropenia is typically dose-dependent.

Patients who are febrile, acutely ill, or with severe neutropenia often warrant urgent hospitalization for close monitoring and treatment. Offending medications must be discontinued as drug-induced agranulocytosis presents up to a 10% mortality and is very likely to recur if the offending agent is restarted.

Complications

There are no intrinsic complications of neutropenia, however people who are neutropenic are at risk for infections and febrile neutropenia.

Febrile Neutropenia

Low risk patients: ANC>100 cells/microliter, normal liver and renal function, normal chest x-ray, no evidence of central line infection, MASCC >21, and duration of neutropenia expected <7 days in a patient with close monitoring and access to medical care.
  • Ciprofloxacin 500mg PO BID + amoxicillin/clavulanate 500mg PO TID
High risk patients: Hospitalize and initiate empiric parenteral antimicrobial therapy. IDSA guidelines recommend initial monotherapy as below.
  • Cefepime 2 g IV Q8H
  • Meropenem 1 g IV Q8H
  • Imipenem/cilastatin 500 mg IV Q6H
  • Piperacillin/tazobactam 4.5 g IV Q6H
  • Ceftazidime 2 g IV Q8H (recent data shows increasing resistance to ceftazidime and inferior Gram-positive coverage to alternative regimens)
Indications for resistant Gram-positive coverage: Vancomycin or linezolid is NOT recommended as part of initial treatment unless one of the following is present and, if started, should be discontinued after 2-3 days if there is no evidence of Gram-positive infection.
Persistent Fever: Continue empiric therapy until either culture data is available to direct management or after 3-5 days if the patient fails to improve. The median time to defercescence in adequately treated patients is 5 days with hematologic malignancies and 2-3 days with solid tumors. If the patient is still febrile or develops recurrent fevers after this time period further work up is suggested.
  1. Re-evaluate sources of infection
  2. Re-evaluate indications for resistant Gram-positive coverage and consider adding vancomycin or linezolid.
  3. Re-evaluate indications for resistant Gram-negative organisms and anaerobes and consider broadening to carbapenem antibiotics.
  4. Consider fungal coverage in high risk patients if fevers persist after 4-7 days of appropriate antibiotic coverage and duration of neutropenia is expected to last >7 days. :Consider the following antifungals.
Caspofungin provides excellent coverage for Candida and is well tolerated, however nodular pulmonary infiltrates warrant coverage of Aspergillus with Voriconazole or Amphotericin B as echinocandins do not provide adequate coverage of Aspergillus or endemic fungi.
Duration of Antimicrobials
  • Documented infection: Continue antimicrobials as directed by culture data. Continue treatment for the standard duration for that particular infection and until myeloid recovery (ANC>500 cells/microliter). If counts recover prior to completing the treatment course, consider transition to an oral regimen guided by culture data.
  • Negative Cultures: Continue empiric antimicrobial regimen until myeloid recovery (ANC>500 cells/microliter). If afebrile with no evidence of ongoing infection, consider transition to oral regimen (e.g. Ciprofloxacin + Amoxicillin/Clavulanate) and continue until myeloid recovery.

Surgery

There are no surgical treatments for neutropenia. In patients' with neutropenic fever, surgical intervention may be necessary depending on the sources of their infections.

Primary Prevention

Prevention of neutropenia is dependent upon avoiding certain medications or treatment of underlying conditions.

Secondary Prevention

Secondary prevention of neutropenia relies on careful avoidance of triggers, such as certain medications, or treatment of underlying conditions. Further discussion of the causes of neutropenia are reviewed above.

References

  1. ↑ Dameshek W. (1944). "Leukopenia and Agranulocytosis". Oxford University Press. 1: 841–52. Text "NLM ID 39120200R" ignored (help)
  2. ↑ Andrès E, Maloisel F. (2008). "Idiosyncratic drug-induced agranulocytosis or acute neutropenia". Curr Opin Hematol. 15 (1): 15–21. PMID 18043241.
  3. ↑ Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. (2011). "Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america". Clin Infect Dis. 52 (4): e56–95. PMID 21258094.
  4. ↑ Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, Kuderer NM, Langston AA, Marr KA, Rolston KV, Ramsey SD (2013). "Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline=J Clin Oncol". 31 (6): 794–810. PMID 23319691.

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