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{{CMG}}; {{AE}}  {{DG}}  {{N.F}}
{{CMG}} {{shyam}}; {{AE}}  {{DG}}  {{N.F}}


'''''Synonyms and Keywords''''': Agranulosis, granulocytopenia, neutropenia
'''''Synonyms and Keywords''''': Agranulosis, granulocytopenia, neutropenia
==Overview==
==Overview==
'''[[Agranulocytosis]]''' is a [[Hematology|hematological]] disorder characterized by the acute-onset of severe [[neutropenia]]. Neutrophils - a subset of [[white blood cell]] - normally make up 50-70% of circulating white blood cells and serve as the primary defense against [[infection]]s. Hence, patients with neutropenia are more susceptible to infections, mainly bacterial; without prompt medical attention, the condition is often life-threatening. Similar to severe neutropenia in the setting of infection, cases related to [[cytotoxic]] [[chemotherapy]], [[hematopoietic stem cell]] transplant, or other causes of [[bone marrow suppression]] are considered a medical emergency.
Agranulocytosis is defined as marked reduction in the number of [[Granulocyte|granulocytes]] ([[Neutrophils]], [[Basophils]], [[Eosinophils]]) below an absolute count of 500 cells/mcL. It is a rare condition with [[incidence]] of 1 to 5 cases per million population per year. Agranulocytosis results in frequent chronic [[Bacterial infection|bacterial infections]] of skin, [[lung]], and [[throat]]. Patients can present with [[sepsis]] and [[fever]]. Among many risk factors, [[Medications|medications,]] combination therapy with [[Angiotensin Converting Enzyme Inhibitor|ACE inhibitors]] and [[interferon]], [[List of chemotherapeutic agents#Cytotoxic Chemotherapy|cytotoxic chemotherapy]], [[Hematologic malignancy|hematologic malignancies]], and [[Autoimmunity|autoimmune disorders]] are the more common. On the basis of [[etiology]] agranulocytosis can be classified as [[congenital]] and [[Acquired|acquired.]] Common causes of [[acquired]] agranulocytosis include medications like [[clozapine]], [[sulfasalazine]], and [[thioamide]], [[Infection|infections]], [[List of illnesses caused by poor nutrition|nutritional deficiencies]], [[Myelodysplastic syndrome|myelodysplasia]], [[Systemic autoimmune diseases|collagen vascular diseases]], and [[Aplasia|white cell aplasia.]] Agranulocytosis needs to be differentiated from bacterial [[sepsis|sepsis,]] [[aplastic anemia]], [[acute myeloid leukemia]], [[acute lymphoblastic leukemia]], [[cytomegalovirus]], [[Folate deficiency|folic acid deficiency]], and [[Hodgkin's lymphoma|Hodgkin lymphoma]]. The negative [[Prognosis|prognostic factors]] in the course of agranulocytosis are age > 65, [[septic shock]], [[bacteremia]], [[Infections|systemic infections]], [[renal]], [[cardiac]] and [[respiratory]] diseases.The mainstay of treatment of agranulocytosis is medical therapy, including, discontinuation of offending agent, treating [[Infection|infections]] with [[Antibiotics|broad spectrum antibiotics,]] and using [[Granulocyte colony stimulating factor|granulocyte-colony stimulating factor]].
 
Agranulocytosis is defined as severe neutropenia with an [[absolute neutrophil count]] (ANC) <500 cells/microliter.
 
While agranulocytosis technically refers to a reduction in all cells in the leukocyte lineage ([[neutrophils]], [[eosinophils]], and [[basophils]]), the vast majority of cases refer to neutropenia as neutrophils constitute the majority of leukocytes and the primary defense against infection.


==Historical Perspective==
==Historical Perspective==
* Agranulocytosis 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>
* Agranulocytosis was first noted around the beginning 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>
 
==Classification==
==Classification==
[[Agranulocytosis]] is often used interchangeably with severe [[neutropenia]]. Calculated based on complete blood count differential, [[agranulocytosis]] is loosely defined as an [[absolute neutrophil count]] (ANC) less than 500, 200, or 100 cells per microliter, with mild and moderate neutropenia defined below.<ref name="PMID17470834">{{cite journal |author=Andersohn F, Konzen C, Garbe E. |title=Systematic review: agranulocytosis induced by nonchemotherapy drugs.|journal=Ann Internal Med.|volume=146(9)|pages=657-65|year=2007|PMID 17470834}}</ref> The ANC is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (including both mature neutrophils and band forms).
Agranulocytosis can be classified as [[Congenital disorder|congenital]] or [[Acquired disorder|acquired]]. Each class can be classified to further subgroups as follows:


* '''Mild Neutropenia:''' ANC 1,000-1500 cells/microliter
===== Congenital =====
* '''Moderate Neutropenia:''' ANC 500-1000 cells/microliter
* [[Kostmann syndrome|Kostmann's syndrome]]
* '''Severe Neutropenia or [[Agranulocytosis]]:''' ANC <500 cells/microliter
* [[Dysgenesis|Reticular dysgenesis]]
* [[Shwachman-Diamond syndrome]]
* [[Chediak-Higashi syndrome]]
* [[Dyskeratosis congenita]]


This distinction is important diagnostically and prognostically. Patients with ANC <500 cells/microliter are at a markedly increased risk for severe infections and those <100 cells/microliter have just over a 3-fold increased risk of mortality<ref name="PMID17470834">{{cite journal |author=Andersohn F, Konzen C, Garbe E. |title=Systematic review: agranulocytosis induced by nonchemotherapy drugs.|journal=Ann Internal Med.|volume=146(9)|pages=657-65|year=2007|PMID 17470834}}</ref> Importantly, due to severely limited neutrophil activity an inflammatory response, these patients may present with a fever absent additional localizing signs of infection.
===== Acquired =====
* Drug induced
** [[Clozapine]]
** [[Sulfasalazine]]
** [[Thioamide]]
* [[Infection]]
** [[Virus|Viral infections]] including:
*** [[Hepatitis B]]
*** [[Hepatitis C]]
*** [[Epstein Barr virus|Epstein-Barr virus]]
*** [[HIV]]
** [[Bacterial]]
** [[Rickettsial]]
* [[Systemic autoimmune diseases|Collagen vascular diseases]]
** [[SLE]]
** [[Felty's syndrome]]
* White cell [[aplasia]]
* [[List of illnesses caused by poor nutrition|Nutritional deficiency]]
** [[Vitamin B12 deficiency]]
** [[Folate deficiency|Folic acid deficiency]]
* [[Myelodysplasia]]
* [[Hypoplasia]]
** [[Aplastic anemia]]
** [[Fanconi's anemia]]
* [[Leukemia]]


==Pathophysiology==
==Pathophysiology==
Agranulocytosis develops as a result of the following mechanisms:<ref name="PontikoglouPapadaki2010">{{cite journal|last1=Pontikoglou|first1=Charalampos|last2=Papadaki|first2=Helen A.|title=Idiosyncratic Drug-Induced Agranulocytosis: The Paradigm of Deferiprone|journal=Hemoglobin|volume=34|issue=3|year=2010|pages=291–304|issn=0363-0269|doi=10.3109/03630269.2010.484791}}</ref>
Agranulocytosis develops as a result of the following mechanisms:<ref name="PontikoglouPapadaki2010">{{cite journal|last1=Pontikoglou|first1=Charalampos|last2=Papadaki|first2=Helen A.|title=Idiosyncratic Drug-Induced Agranulocytosis: The Paradigm of Deferiprone|journal=Hemoglobin|volume=34|issue=3|year=2010|pages=291–304|issn=0363-0269|doi=10.3109/03630269.2010.484791}}</ref>
* '''Immune mediated destruction of granulocytes'''
* '''[[Immune mediated]] destruction of [[granulocytes]]'''
** The drugs or its active metabolite act as hapten, and binds to neutrophil membrane.
** The drugs or its active [[metabolite]] act as [[hapten]], and binds to [[neutrophil]] [[membrane]].
** Autoantibodies are produced as a result of this binding.
** [[Autoantibodies]] are produced as a result of this binding.
** This results in destruction of sensetized neutrophils by phagocytosis.
** This results in destruction of sensitized [[neutrophils]] by [[phagocytosis]].
** Most common drugs are,  propylthiouracil, amodiaquine , mono-desethyl amodiaquine, and flecainide  
** Most common drugs are [[propylthiouracil]], [[amodiaquine]], [[Amodiaquine|mono-desethyl amodiaquine]], and [[flecainide]].


* '''Direct damage of granulocytes'''
* '''Direct damage of [[Granulocyte|granulocytes]]'''
** Some drugs releases chemically active metabolites.
** Some drugs release chemically active [[metabolites]].
** These metabolites bind to cytoplasmic proteins or proteins in the nucleus.
** These metabolites bind to [[Proteins|cytoplasmic proteins]] or [[proteins]] in the [[nucleus]].
** This results in direct toxicity and destruction of granulocytes.
** This results in direct [[toxicity]] and destruction of [[granulocytes]].
** Chlorpromazine. dapsone, clozapine and procainamide are few examples of the drugs.
** [[Chlorpromazine]], [[dapsone]], [[clozapine]], and [[procainamide]] are few examples of these drugs.
** Granulocytes oxidize clozapine releasing nitrenium ions.<ref name="UetrechtZahid1997">{{cite journal|last1=Uetrecht|first1=Jack|last2=Zahid|first2=Nasir|last3=Tehim|first3=Ashik|last4=Mim Fu|first4=J|last5=Rakhit|first5=Suman|title=Structural features associated with reactive metabolite formation in clozapine analogues|journal=Chemico-Biological Interactions|volume=104|issue=2-3|year=1997|pages=117–129|issn=00092797|doi=10.1016/S0009-2797(97)00017-3}}</ref>
** [[Granulocytes]] oxidize [[clozapine]] releasing [[Nitrenium ion|nitrenium ions]].<ref name="UetrechtZahid1997">{{cite journal|last1=Uetrecht|first1=Jack|last2=Zahid|first2=Nasir|last3=Tehim|first3=Ashik|last4=Mim Fu|first4=J|last5=Rakhit|first5=Suman|title=Structural features associated with reactive metabolite formation in clozapine analogues|journal=Chemico-Biological Interactions|volume=104|issue=2-3|year=1997|pages=117–129|issn=00092797|doi=10.1016/S0009-2797(97)00017-3}}</ref>
** Nitrenium ions bind irreversibly to granulocytes and its precursor cells resulting in toxic destruction of these cells.
** [[Nitrenium ion|Nitrenium ions]] bind irreversibly to [[granulocytes]] and its [[precursor]] cells resulting in [[toxic]] destruction of these [[Cell (biology)|cells]].


==Causes==
==Causes==
Agranulocytosis can be congenital or acquired. Common causes of acquired agranulocytosis include:<ref name="PMID17470834" /><ref name="AndersohnKonzen2007">{{cite journal|last1=Andersohn|first1=Frank|last2=Konzen|first2=Christine|last3=Garbe|first3=Edeltraut|title=Systematic Review: Agranulocytosis Induced by Nonchemotherapy Drugs|journal=Annals of Internal Medicine|volume=146|issue=9|year=2007|pages=657|issn=0003-4819|doi=10.7326/0003-4819-146-9-200705010-00009}}</ref>
Agranulocytosis can be [[congenital]] or [[acquired]]. Common causes of acquired agranulocytosis include:<ref name="PMID17470834">{{cite journal |author=Andersohn F, Konzen C, Garbe E. |title=Systematic review: agranulocytosis induced by nonchemotherapy drugs.|journal=Ann Internal Med.|volume=146(9)|pages=657-65|year=2007|PMID 17470834}}</ref><ref name="AndersohnKonzen2007">{{cite journal|last1=Andersohn|first1=Frank|last2=Konzen|first2=Christine|last3=Garbe|first3=Edeltraut|title=Systematic Review: Agranulocytosis Induced by Nonchemotherapy Drugs|journal=Annals of Internal Medicine|volume=146|issue=9|year=2007|pages=657|issn=0003-4819|doi=10.7326/0003-4819-146-9-200705010-00009}}</ref>
* Medications
* Medications
** Clozapine
** [[Clozapine]]
** Deferiprone
** [[Deferiprone]]
** Thionamides
** [[Sulfasalazine]]
** Sulfasalazine
** [[Ticlopidine]]
** Ticlopidine
** [[Rituximab]]
** Rituximab
** [[Quinine]]
** Quinine
** [[Trimethoprim-sulfamethoxazole]]
** Trimethoprim-sulfamethoxazole  


* Chemotherapy  
* [[Chemotherapy]]
* Bone marrow transplant  
* [[Bone marrow transplant]]
* Systemic Lupus erythramatosis
* [[Systemic lupus erythematosus]] ([[SLE]])
* Rheumatoid arthritis  
* [[Rheumatoid arthritis]]
* HIV  
* [[HIV]]
* Hepatitis  
* [[Hepatitis]]
* Leukemia  
* [[Leukemia]]
* Myelodysplasia  
* [[Myelodysplasia]]


==Differentiating Agranulocytosis from Other Diseases==
==Differentiating Agranulocytosis from Other Diseases==
[[Agranulocytosis]] is a laboratory diagnosis based off of the [[complete blood count]] differential, however the differential diagnosis for the etiology of neutropenia and agranulocytosis is quite important as patients can deteriorate rapidly without appropriate treatment.


Consider the following differential when evaluating a patient with agranulocytosis:
Consider the following differential when evaluating a patient with agranulocytosis:
*'''Drug-induced''': An idiosyncratic (dose-independent) reaction. Accounts for 65-75% of all cases of agranulocytosis in the United States. More commonly presents with isolated neutropenia in the absence of [[anemia]] or [[thrombocytopenia]].<ref>{{cite journal |vauthors=Andersohn F, Konzen C, Garbe E |title=Systematic review: agranulocytosis induced by nonchemotherapy drugs |journal=Ann. Intern. Med. |volume=146 |issue=9 |pages=657–65 |date=May 2007 |pmid=17470834 |doi=10.7326/0003-4819-146-9-200705010-00009 |url=http://annals.org/article.aspx?articleid=734449}}</ref>
* Bacterial [[sepsis]]
*'''Malignant''': Typically, a dose-dependent reduction in neutrophils to cytotoxic chemotherapy, malignant infiltration of the bone marrow, or immune-mediated hemolysis. Often seen concurrently with severe anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy.
* [[Aplastic anemia]]
*'''Autoimmune''': Antibody-mediated neutrophil destruction.<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>
* [[Acute myeloid leukemia]]
* [[Acute lymphoblastic leukemia]]
* [[Cytomegalovirus]]
* [[Folic acid deficiency]]
* [[Hodgkin lymphoma]]
* [[Non-Hodgkin lymphoma]]
* [[Wegener granulomatosis]]


==Epidemiology and Demographics==
==Epidemiology and Demographics==
* Agranulocytosis is extremly rare condition
* Agranulocytosis is an extremely [[rare]] condition.
* The overall incidence rate is 7.2 per million per year<ref name="Strom1992">{{cite journal|last1=Strom|first1=Brian L.|title=Descriptive Epidemiology of Agranulocytosis|journal=Archives of Internal Medicine|volume=152|issue=7|year=1992|pages=1475|issn=0003-9926|doi=10.1001/archinte.1992.00400190095018}}</ref>
* The overall [[Incidence (epidemiology)|incidence rate]] is 7.2 per million per year.<ref name="Strom1992">{{cite journal|last1=Strom|first1=Brian L.|title=Descriptive Epidemiology of Agranulocytosis|journal=Archives of Internal Medicine|volume=152|issue=7|year=1992|pages=1475|issn=0003-9926|doi=10.1001/archinte.1992.00400190095018}}</ref>
* It can occur in all races and any age group
* It can occur in all [[Race|races]] and any age group.
* The acquired type of agraulocytosis is more common in older individuals
* The [[acquired]] type of agranulocytosis is more common in older individuals. While [[inherited]] type is commonly seen in children.
* Inherited type is commonly seen in children.
* The risk of agranulocytosis is seen higher in women.<ref name="AlvirLieberman1993">{{cite journal|last1=Alvir|first1=Jose Ma. J.|last2=Lieberman|first2=Jeffrey A.|last3=Safferman|first3=Allan Z.|last4=Schwimmer|first4=Jeffrey L.|last5=Schaaf|first5=John A.|title=Clozapine-Induced Agranulocytosis -- Incidence and Risk Factors in the United States|journal=New England Journal of Medicine|volume=329|issue=3|year=1993|pages=162–167|issn=0028-4793|doi=10.1056/NEJM199307153290303}}</ref>
* The risk of agranulocytosis is seen higher in women<ref name="AlvirLieberman1993">{{cite journal|last1=Alvir|first1=Jose Ma. J.|last2=Lieberman|first2=Jeffrey A.|last3=Safferman|first3=Allan Z.|last4=Schwimmer|first4=Jeffrey L.|last5=Schaaf|first5=John A.|title=Clozapine-Induced Agranulocytosis -- Incidence and Risk Factors in the United States|journal=New England Journal of Medicine|volume=329|issue=3|year=1993|pages=162–167|issn=0028-4793|doi=10.1056/NEJM199307153290303}}</ref>


==Risk Factors==
==Risk Factors==
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** [[Autoimmune disorders]]
** [[Autoimmune disorders]]
* Genetic susceptibility
* Genetic susceptibility
** Association between HLA-B38, DQW3 haplotype and clozapine induced agranulocytosis is seen in Ashkenazi Jews<ref name="pmid7579351">{{cite journal |vauthors=Corzo D, Yunis JJ, Salazar M, Lieberman JA, Howard A, Awdeh Z, Alper CA, Yunis EJ |title=The major histocompatibility complex region marked by HSP70-1 and HSP70-2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups |journal=Blood |volume=86 |issue=10 |pages=3835–40 |date=November 1995 |pmid=7579351 |doi= |url=}}</ref>
** Association between [[HLA-B]]38, DQW3 haplotype, and [[clozapine]] induced agranulocytosis is seen in Ashkenazi Jews.<ref name="pmid7579351">{{cite journal |vauthors=Corzo D, Yunis JJ, Salazar M, Lieberman JA, Howard A, Awdeh Z, Alper CA, Yunis EJ |title=The major histocompatibility complex region marked by HSP70-1 and HSP70-2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups |journal=Blood |volume=86 |issue=10 |pages=3835–40 |date=November 1995 |pmid=7579351 |doi= |url=}}</ref>
** HLA DRB1*08032 allele has a strong suseptibility to methimazole induced agranulocytosis<ref name="Tamai1996">{{cite journal|last1=Tamai|first1=Hajime|title=Association between the DRB1*08032 Histocompatibility Antigen and Methimazole-Induced Agranulocytosis in Japanese Patients with Graves Disease|journal=Annals of Internal Medicine|volume=124|issue=5|year=1996|pages=490|issn=0003-4819|doi=10.7326/0003-4819-124-5-199603010-00005}}</ref>
** [[HLA-DRB1|HLA DRB1]]*08032 allele has a strong susceptibility to [[methimazole]] induced agranulocytosis.<ref name="Tamai1996">{{cite journal|last1=Tamai|first1=Hajime|title=Association between the DRB1*08032 Histocompatibility Antigen and Methimazole-Induced Agranulocytosis in Japanese Patients with Graves Disease|journal=Annals of Internal Medicine|volume=124|issue=5|year=1996|pages=490|issn=0003-4819|doi=10.7326/0003-4819-124-5-199603010-00005}}</ref>


==Screening==
==Screening==
There are no routine screening recommendations for [[agranulocytosis]]. It is typically identified incidentally on routine blood work or while monitoring after cytotoxic therapy.<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>
There are no routine screening recommendations for agranulocytosis. It is typically identified incidentally on routine blood work or while monitoring after [[cytotoxic]] therapy.<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>


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
===Natural History===
===Natural History===
* [[Neutropenia]], and progression to [[agranulocytosis]], occurs in either a dose-dependent or idiosyncratic process dependent upon the etiology.  
* [[Neutropenia]], and progression to agranulocytosis, occurs in either a dose-dependent or [[Idiosyncratic reaction|idiosyncratic]] process dependent upon the [[etiology]].  


* Neutropenia caused by [[cytotoxic]] [[chemotherapy]] or malignant bone marrow infiltration is typically dose-dependent or related to tumor burden, as opposed to  
* Neutropenia caused by [[cytotoxic]] [[chemotherapy]] or malignant [[bone marrow]] infiltration is typically dose-dependent or related to tumor burden, as opposed to idiosyncratic, and  [[Immune-mediated disease|immune-mediated]] [[neutropenia]] that occurs independently.  
* Idiosyncratic, and  immune-mediated neutopenia occur independently.


===Complications===
===Complications===
The major complications of agranulocytosis are as follows<ref name="AndrèsMaloisel20102">{{cite journal|last1=Andrès|first1=Emmanuel|last2=Maloisel|first2=Frédéric|last3=Zimmer|first3=Jacques|title=The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis|journal=British Journal of Haematology|year=2010|issn=00071048|doi=10.1111/j.1365-2141.2010.08104.x}}</ref>
The major complications of agranulocytosis are as follows:<ref name="AndrèsMaloisel20102">{{cite journal|last1=Andrès|first1=Emmanuel|last2=Maloisel|first2=Frédéric|last3=Zimmer|first3=Jacques|title=The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis|journal=British Journal of Haematology|year=2010|issn=00071048|doi=10.1111/j.1365-2141.2010.08104.x}}</ref>
* Septicemia
* [[Septicemia]]
* Bacterial infections
* [[Bacterial infections]]
* Fungal infections
* [[Fungal infections]]
* Pneumonia
* [[Pneumonia]]
* Fever
* [[Fever]]
* Mouth ulcers
* [[Mouth ulcers]]


===Prognosis===
===Prognosis===
The negative prognostic factors for agranulocytosis are:<ref name="AndrèsMaloisel2010">{{cite journal|last1=Andrès|first1=Emmanuel|last2=Maloisel|first2=Frédéric|last3=Zimmer|first3=Jacques|title=The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis|journal=British Journal of Haematology|year=2010|issn=00071048|doi=10.1111/j.1365-2141.2010.08104.x}}</ref>
The negative prognostic factors for agranulocytosis are:<ref name="AndrèsMaloisel2010">{{cite journal|last1=Andrès|first1=Emmanuel|last2=Maloisel|first2=Frédéric|last3=Zimmer|first3=Jacques|title=The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis|journal=British Journal of Haematology|year=2010|issn=00071048|doi=10.1111/j.1365-2141.2010.08104.x}}</ref>
* Neutrophil count at the time of diagnosis <0.1 × 109/l
* [[Neutrophil|Neutrophil count]] at the time of diagnosis <0.1 × 10<sup>9</sup> cells/L


* Age > 65yrs
* Age > 65 years old
* Advancement in to severe infections like se[tic shock, bacteremia
* Severe infections like [[septic shock]], [[bacteremia]]
* Pre existance of systemic infections, renal, cardiac and respiratory diseases.
* Pre existence of systemic infections, [[renal]], [[cardiac]] and [[respiratory]] diseases


==History and Symptoms==
==Diagnosis==


==== History ====
=== Diagnostic Study of Choice ===
History of patients with agranulocytosis should focus on any history of:
The diagnosis of agranulocytosis is based on the laboratory finding when the number of [[Granulocyte|granulocytes]] ([[Neutrophils]], [[Basophils]], [[Eosinophils]]) is below an absolute count of 500 cells/mcL.
* Malignancy
* Infection
* Autoimmune disorders
* Medications


==== Symptoms ====
=== History and Symptoms ===
Common symptoms include:
History of patients with agranulocytosis should focus on any history of:<ref name="AndrèsZimmer2014">{{cite journal|last1=Andrès|first1=Emmanuel|last2=Zimmer|first2=Jacques|last3=Mecili|first3=Mustapha|last4=Weitten|first4=Thierry|last5=Alt|first5=Martine|last6=Maloisel|first6=Frédéric|title=Clinical presentation and management of drug-induced agranulocytosis|journal=Expert Review of Hematology|volume=4|issue=2|year=2014|pages=143–151|issn=1747-4086|doi=10.1586/ehm.11.12}}</ref>
* [[Malignancy]]
* [[Infection]]
* [[Autoimmune disorders]]
* [[Medication|Medications]]
Common symptoms include:<ref name="AndrèsZimmer2014" />
*[[Fever]]
*[[Fever]]
*Frequent [[infections]]
*Symptoms of frequent [[infections]]
*Unusual [[redness]], [[pain]], or [[swelling]] around a wound
*Unusual [[redness]], [[pain]], or [[swelling]] around a wound
*Mouth [[ulcers]]
*Mouth [[ulcers]]
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*Shaking [[chills]]
*Shaking [[chills]]


==Physical Examination==
===Physical Examination===
Common signs of agranulocytosis may include:
Common signs of agranulocytosis may include:
*[[Fever]]
*[[Fever]]
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*[[Hyperbilirubinemia|Jaundice]]
*[[Hyperbilirubinemia|Jaundice]]
*[[Wheeze|Wheezes]]
*[[Wheeze|Wheezes]]
*[[rales]]
*[[Rales]]
*[[Joint swelling]] or deformity
*[[Joint swelling]] or deformity
*[[Rashes]]
*[[Rashes]]
===Laboratory Findings===
===Laboratory Findings===
The following tests should be performed after careful medication history:
* [[CBC]]
* Differential [[WBC]]
* [[Peripheral blood smear]]
Some patients may need:
* [[Liver function tests]]
* [[Rheumatoid factor]]
* Peripheral [[Flow cytometry|blood flow cytometry]]
* [[Anti-nuclear antibody|Antinuclear antibody]] ([[Antinuclear antibodies|ANA]])
* [[Immunoglobulin|Serum immunoglobulin study]]
* [[Vitamin B12]] and [[Folate levels]]
* [[HIV]] testing
=== Electrocardiogram ===
There are no ECG findings associated with agranulocytosis.
=== X-ray ===
There are no x-ray findings associated with agranulocytosis. However, an x-ray may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.
=== Echocardiography or Ultrasound ===
There are no echocardiography/ultrasound findings associated with agranulocytosis.
=== CT scan ===
There are no CT scan findings associated with agranulocytosis. However, a CT scan may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.
=== MRI ===
There are no MRI findings associated with agranulocytosis. However, a MRI may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.
=== Other Imaging Findings ===
There are no other imaging findings associated with agranulocytosis.
=== Other Diagnostic Studies ===
There are no other diagnostic studies associated with agranulocytosis.


==Treatment==
==Treatment==
==Medical Therapy==
===Medical Therapy===
* Discontinuation of the offending agent
* '''Discontinuation of the offending agent'''
** Identifying and removing the offending agents
** Identifying and removing the offending agents
** It takes about 1-3 weeks for neutropenia to resolve after stopping the offending drug
** It takes about 1-3 weeks for [[neutropenia]] to resolve after stopping the offending drug.


* Treat the associated infections and conditions
* '''Treat the associated infections and conditions'''
** In cases of [[febrile neutropenia]], [[empiric]] [[antibiotics]] should be administered intravenously as early as possible
** In cases of [[febrile neutropenia]], [[Empiric therapy|empiric antibiotics]] should be administered [[intravenously]] as early as possible.<ref name="TesfaKeisu2009">{{cite journal|last1=Tesfa|first1=Daniel|last2=Keisu|first2=Marianne|last3=Palmblad|first3=Jan|title=Idiosyncratic drug-induced agranulocytosis: Possible mechanisms and management|journal=American Journal of Hematology|volume=84|issue=7|year=2009|pages=428–434|issn=03618609|doi=10.1002/ajh.21433}}</ref>
** Before starting the antibiotics, blood, urine and sputum cultures should be withdrawn
** Before starting the [[Antibiotic|antibiotics]], blood, urine and [[Sputum culture|sputum cultures]] should be withdrawn.
** Antibiotic coverage should be bactericidal for most common pathogens<ref name="PMID4994878">{{cite journal |author=Schimpff S, Satterlee W, Young VM, Serpick A |title=Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia |journal=N Engl J Med. |volume=284 |issue=19 |pages=1061-5 |year=1971 |pmid=4994878 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/4994878}}</ref><ref name="PMID16625125">{{cite journal |author=Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M |title=Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock |journal=Crit Care Med. |volume=34 |issue=6 |pages=1589-96 |year=2006 |pmid=16625125 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/16625125}}</ref><ref name="PMID24752269">{{cite journal |author=Rosa RG, Goldani LZ. |title=Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia |journal=Antimicrob Agents Chemother. |volume=58 |issue=7|pages=3799-803 |year=2014 |pmid=24752269 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/24752269}}</ref>
** [[Antibiotic]] coverage should be [[bactericidal]] for most common [[pathogens]].<ref name="PMID4994878">{{cite journal |author=Schimpff S, Satterlee W, Young VM, Serpick A |title=Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia |journal=N Engl J Med. |volume=284 |issue=19 |pages=1061-5 |year=1971 |pmid=4994878 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/4994878}}</ref><ref name="PMID16625125">{{cite journal |author=Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M |title=Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock |journal=Crit Care Med. |volume=34 |issue=6 |pages=1589-96 |year=2006 |pmid=16625125 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/16625125}}</ref><ref name="PMID24752269">{{cite journal |author=Rosa RG, Goldani LZ. |title=Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia |journal=Antimicrob Agents Chemother. |volume=58 |issue=7|pages=3799-803 |year=2014 |pmid=24752269 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/24752269}}</ref>
** Central venous catheters and other indwelling devices should be removed when possible if there is suspicion for infection or with positive blood cultures.
** [[Central venous catheters]] and other indwelling devices should be removed when possible if there is suspicion for [[infection]] or with positive [[Blood culture|blood cultures]].
* Use of [[granulocyte-colony stimulating factor]]
* '''Use of granulocyte-colony stimulating factor'''
**  [[Granulocyte colony stimulating factor|Granulocyte-colony stimulating factor]] (G-CSF) has shown excellent results in patients with drug induced agranulocytosis and severe [[Infection|infection.]]<ref name="AndrèsZimmer2014" />
** It is mostly beneficial in patients with [[neutropenia]] secondary to [[chemotherapy]].


** G-CSF has shown excellent results in patients with drug induced agranulocytosis and severe infection.
* '''Immune suppression'''
** It is very beneficial in patiets with neutropenia secondry to chemotherapy
** In [[neutropenia]] with [[autoimmune diseases]], [[prednisone]] is used for [[immunosuppression]].


* Immune suppression
* '''Bone marrow transplant'''
** In neutropenia with autoimmune diseases, prednisone is used for immune suppression
** When other treatments do not work, [[Bone marrow transplantation|bone marrow transplant]] is an option.
 
** It is more successful in patients aged <40 years old in good health.
* Bone marrow transplant
** When other treatments do not work, bone marrow transplant is an option
** It is more successful in patients aged<40 yrs and with good health.


===Surgery===
===Surgery===
There are no surgical treatments for [[agranulocytosis]]. In patients with [[neutropenic fever]], surgical intervention may be necessary depending on the source of infection.<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>
There are no surgical treatments for agranulocytosis. However, in patients with [[neutropenic fever]], surgical intervention may be necessary depending on the source of infection.<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>
 
===Prevention===
Prevention of [[agranulocytosis]] is dependent upon avoiding certain medications or treatment of underlying conditions.  Occasionally, when agranulocytosis is anticipated, such as in the setting of cytotoxic chemotherapy, recombinant [[Granulocyte-colony stimulating factor|G-CSF]] (granulocyte-colony stimulating factor) can be considered to speed myeloid reconstitution.


===Primary Prevention===
Primary prevention of agranulocytosis is dependent upon:
* Avoiding certain [[medications]]
* Occasionally, when agranulocytosis is anticipated, such as in the setting of [[Chemotherapy|cytotoxic chemotherapy]], recombinant [[Granulocyte-colony stimulating factor|G-CSF]] ([[Granulocyte colony stimulating factor|granulocyte-colony stimulating factor]]) can be considered to speed [[myeloid]] reconstitution.
===Secondary Prevention===
Effective measures for the secondary prevention of agranulocytosis include early detection and treatment of underlying conditions.
==See also==
==See also==
* [[Complete blood count]]
* [[Complete blood count]]
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[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Hematology]]
 
[[Category:Infectious disease]]
{{WS}}
[[Category:Oncology]]
{{WH}}
[[Category:Up-To-Date]]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]; Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [3] Nazia Fuad M.D.

Synonyms and Keywords: Agranulosis, granulocytopenia, neutropenia

Overview

Agranulocytosis is defined as marked reduction in the number of granulocytes (Neutrophils, Basophils, Eosinophils) below an absolute count of 500 cells/mcL. It is a rare condition with incidence of 1 to 5 cases per million population per year. Agranulocytosis results in frequent chronic bacterial infections of skin, lung, and throat. Patients can present with sepsis and fever. Among many risk factors, medications, combination therapy with ACE inhibitors and interferon, cytotoxic chemotherapy, hematologic malignancies, and autoimmune disorders are the more common. On the basis of etiology agranulocytosis can be classified as congenital and acquired. Common causes of acquired agranulocytosis include medications like clozapine, sulfasalazine, and thioamide, infections, nutritional deficiencies, myelodysplasia, collagen vascular diseases, and white cell aplasia. Agranulocytosis needs to be differentiated from bacterial sepsis, aplastic anemia, acute myeloid leukemia, acute lymphoblastic leukemia, cytomegalovirus, folic acid deficiency, and Hodgkin lymphoma. The negative prognostic factors in the course of agranulocytosis are age > 65, septic shock, bacteremia, systemic infections, renal, cardiac and respiratory diseases.The mainstay of treatment of agranulocytosis is medical therapy, including, discontinuation of offending agent, treating infections with broad spectrum antibiotics, and using granulocyte-colony stimulating factor.

Historical Perspective

  • Agranulocytosis was first noted around the beginning 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

Agranulocytosis can be classified as congenital or acquired. Each class can be classified to further subgroups as follows:

Congenital
Acquired

Pathophysiology

Agranulocytosis develops as a result of the following mechanisms:[2]

Causes

Agranulocytosis can be congenital or acquired. Common causes of acquired agranulocytosis include:[4][5]

Differentiating Agranulocytosis from Other Diseases

Consider the following differential when evaluating a patient with agranulocytosis:

Epidemiology and Demographics

  • Agranulocytosis is an extremely rare condition.
  • The overall incidence rate is 7.2 per million per year.[6]
  • It can occur in all races and any age group.
  • The acquired type of agranulocytosis is more common in older individuals. While inherited type is commonly seen in children.
  • The risk of agranulocytosis is seen higher in women.[7]

Risk Factors

Risk factors for agranulocytosis include:

Screening

There are no routine screening recommendations for agranulocytosis. It is typically identified incidentally on routine blood work or while monitoring after cytotoxic therapy.[13]

Natural History, Complications, and Prognosis

Natural History

Complications

The major complications of agranulocytosis are as follows:[14]

Prognosis

The negative prognostic factors for agranulocytosis are:[15]

Diagnosis

Diagnostic Study of Choice

The diagnosis of agranulocytosis is based on the laboratory finding when the number of granulocytes (Neutrophils, Basophils, Eosinophils) is below an absolute count of 500 cells/mcL.

History and Symptoms

History of patients with agranulocytosis should focus on any history of:[16]

Common symptoms include:[16]

Physical Examination

Common signs of agranulocytosis may include:

Laboratory Findings

The following tests should be performed after careful medication history:

Some patients may need:

Electrocardiogram

There are no ECG findings associated with agranulocytosis.

X-ray

There are no x-ray findings associated with agranulocytosis. However, an x-ray may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with agranulocytosis.

CT scan

There are no CT scan findings associated with agranulocytosis. However, a CT scan may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.

MRI

There are no MRI findings associated with agranulocytosis. However, a MRI may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.

Other Imaging Findings

There are no other imaging findings associated with agranulocytosis.

Other Diagnostic Studies

There are no other diagnostic studies associated with agranulocytosis.

Treatment

Medical Therapy

  • Discontinuation of the offending agent
    • Identifying and removing the offending agents
    • It takes about 1-3 weeks for neutropenia to resolve after stopping the offending drug.
  • Bone marrow transplant
    • When other treatments do not work, bone marrow transplant is an option.
    • It is more successful in patients aged <40 years old in good health.

Surgery

There are no surgical treatments for agranulocytosis. However, in patients with neutropenic fever, surgical intervention may be necessary depending on the source of infection.[13]

Primary Prevention

Primary prevention of agranulocytosis is dependent upon:

Secondary Prevention

Effective measures for the secondary prevention of agranulocytosis include early detection and treatment of underlying conditions.

See also

References

  1. ↑ Dameshek W. (1944). "Leukopenia and Agranulocytosis". Oxford University Press. 1: 841–52. Text "NLM ID 39120200R" ignored (help)
  2. ↑ Pontikoglou, Charalampos; Papadaki, Helen A. (2010). "Idiosyncratic Drug-Induced Agranulocytosis: The Paradigm of Deferiprone". Hemoglobin. 34 (3): 291–304. doi:10.3109/03630269.2010.484791. ISSN 0363-0269.
  3. ↑ Uetrecht, Jack; Zahid, Nasir; Tehim, Ashik; Mim Fu, J; Rakhit, Suman (1997). "Structural features associated with reactive metabolite formation in clozapine analogues". Chemico-Biological Interactions. 104 (2–3): 117–129. doi:10.1016/S0009-2797(97)00017-3. ISSN 0009-2797.
  4. ↑ Andersohn F, Konzen C, Garbe E. (2007). "Systematic review: agranulocytosis induced by nonchemotherapy drugs". Ann Internal Med. 146(9): 657–65. Text "PMID 17470834" ignored (help)
  5. ↑ Andersohn, Frank; Konzen, Christine; Garbe, Edeltraut (2007). "Systematic Review: Agranulocytosis Induced by Nonchemotherapy Drugs". Annals of Internal Medicine. 146 (9): 657. doi:10.7326/0003-4819-146-9-200705010-00009. ISSN 0003-4819.
  6. ↑ Strom, Brian L. (1992). "Descriptive Epidemiology of Agranulocytosis". Archives of Internal Medicine. 152 (7): 1475. doi:10.1001/archinte.1992.00400190095018. ISSN 0003-9926.
  7. ↑ Alvir, Jose Ma. J.; Lieberman, Jeffrey A.; Safferman, Allan Z.; Schwimmer, Jeffrey L.; Schaaf, John A. (1993). "Clozapine-Induced Agranulocytosis -- Incidence and Risk Factors in the United States". New England Journal of Medicine. 329 (3): 162–167. doi:10.1056/NEJM199307153290303. ISSN 0028-4793.
  8. ↑ Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. (2006). "Idiosyncratic drug-induced agranulocytosis: Update of an old disorder". Eur J Intern Med. 17 (8): 529–35. Text "pmid 17142169" ignored (help)
  9. ↑ Levy M, Kelly JP, Kaufman DW, Shapiro S (October 1993). "Risk of agranulocytosis and aplastic anemia in relation to history of infectious mononucleosis: a report from the international agranulocytosis and aplastic anemia study". Ann. Hematol. 67 (4): 187–90. PMID 8218540.
  10. ↑ Casato, Milyia; Pucillo, Leopoldo P.; Leoni, Marco; di Lullo, Luca; Gabrielli, Armando; Sansonno, Domenico; Dammacco, Franco; Danieli, Giovanni; Bonomo, Lorenzo (1995). "Granulocytopenia after combined therapy with interferon and angiotensin-converting enzyme inhibitors: Evidence for a synergistic hematologic toxicity". The American Journal of Medicine. 99 (4): 386–391. doi:10.1016/S0002-9343(99)80186-7. ISSN 0002-9343.
  11. ↑ Corzo D, Yunis JJ, Salazar M, Lieberman JA, Howard A, Awdeh Z, Alper CA, Yunis EJ (November 1995). "The major histocompatibility complex region marked by HSP70-1 and HSP70-2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups". Blood. 86 (10): 3835–40. PMID 7579351.
  12. ↑ Tamai, Hajime (1996). "Association between the DRB1*08032 Histocompatibility Antigen and Methimazole-Induced Agranulocytosis in Japanese Patients with Graves Disease". Annals of Internal Medicine. 124 (5): 490. doi:10.7326/0003-4819-124-5-199603010-00005. ISSN 0003-4819.
  13. ↑ 13.0 13.1 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.
  14. ↑ Andrès, Emmanuel; Maloisel, Frédéric; Zimmer, Jacques (2010). "The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis". British Journal of Haematology. doi:10.1111/j.1365-2141.2010.08104.x. ISSN 0007-1048.
  15. ↑ Andrès, Emmanuel; Maloisel, Frédéric; Zimmer, Jacques (2010). "The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis". British Journal of Haematology. doi:10.1111/j.1365-2141.2010.08104.x. ISSN 0007-1048.
  16. ↑ 16.0 16.1 16.2 Andrès, Emmanuel; Zimmer, Jacques; Mecili, Mustapha; Weitten, Thierry; Alt, Martine; Maloisel, Frédéric (2014). "Clinical presentation and management of drug-induced agranulocytosis". Expert Review of Hematology. 4 (2): 143–151. doi:10.1586/ehm.11.12. ISSN 1747-4086.
  17. ↑ Tesfa, Daniel; Keisu, Marianne; Palmblad, Jan (2009). "Idiosyncratic drug-induced agranulocytosis: Possible mechanisms and management". American Journal of Hematology. 84 (7): 428–434. doi:10.1002/ajh.21433. ISSN 0361-8609.
  18. ↑ Schimpff S, Satterlee W, Young VM, Serpick A (1971). "Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia". N Engl J Med. 284 (19): 1061–5. PMID 4994878.
  19. ↑ Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M (2006). "Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock". Crit Care Med. 34 (6): 1589–96. PMID 16625125.
  20. ↑ Rosa RG, Goldani LZ. (2014). "Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia". Antimicrob Agents Chemother. 58 (7): 3799–803. PMID 24752269.
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