Agranulocytosis: Difference between revisions

Jump to navigation Jump to search
Line 13: Line 13:


==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]] 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).


* '''Mild Neutropenia:''' ANC 1,000-1500 cells/microliter
* '''Mild Neutropenia:''' ANC 1,000-1500 cells/microliter
Line 19: Line 19:
* '''Severe Neutropenia or [[Agranulocytosis]]:''' ANC <500 cells/microliter
* '''Severe Neutropenia or [[Agranulocytosis]]:''' ANC <500 cells/microliter


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 (10% vs. 3%; p <0.001). <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). Importantly, due to severely limited neutrophil activity an inflammatory response, these patients may present with a fever absent additional localizing signs of infection.
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 (10% vs. 3%; p <0.001).<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). Importantly, due to severely limited neutrophil activity an inflammatory response, these patients may present with a fever absent additional localizing signs of infection.


==Pathophysiology==
==Pathophysiology==

Revision as of 12:39, 30 January 2017

WikiDoc Resources for Agranulocytosis

Articles

Most recent articles on Agranulocytosis

Most cited articles on Agranulocytosis

Review articles on Agranulocytosis

Articles on Agranulocytosis in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Agranulocytosis

Images of Agranulocytosis

Photos of Agranulocytosis

Podcasts & MP3s on Agranulocytosis

Videos on Agranulocytosis

Evidence Based Medicine

Cochrane Collaboration on Agranulocytosis

Bandolier on Agranulocytosis

TRIP on Agranulocytosis

Clinical Trials

Ongoing Trials on Agranulocytosis at Clinical Trials.gov

Trial results on Agranulocytosis

Clinical Trials on Agranulocytosis at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Agranulocytosis

NICE Guidance on Agranulocytosis

NHS PRODIGY Guidance

FDA on Agranulocytosis

CDC on Agranulocytosis

Books

Books on Agranulocytosis

News

Agranulocytosis in the news

Be alerted to news on Agranulocytosis

News trends on Agranulocytosis

Commentary

Blogs on Agranulocytosis

Definitions

Definitions of Agranulocytosis

Patient Resources / Community

Patient resources on Agranulocytosis

Discussion groups on Agranulocytosis

Patient Handouts on Agranulocytosis

Directions to Hospitals Treating Agranulocytosis

Risk calculators and risk factors for Agranulocytosis

Healthcare Provider Resources

Symptoms of Agranulocytosis

Causes & Risk Factors for Agranulocytosis

Diagnostic studies for Agranulocytosis

Treatment of Agranulocytosis

Continuing Medical Education (CME)

CME Programs on Agranulocytosis

International

Agranulocytosis en Espanol

Agranulocytosis en Francais

Business

Agranulocytosis in the Marketplace

Patents on Agranulocytosis

Experimental / Informatics

List of terms related to Agranulocytosis

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

Overview

Agranulocytosis is a 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 infections. Hence, patients with neutropenia are more susceptible to infections, mainly bacterial, and 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 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

Agranulocytosis, or severe 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

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.[2] 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).

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

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 (10% vs. 3%; p <0.001).[2] 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). Importantly, due to severely limited neutrophil activity an inflammatory response, these patients may present with a fever absent additional localizing signs of infection.

Pathophysiology

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

  1. Impaired granulocyte production
  2. Margination: the process by which free flowing blood cells are signaled to adhere to the endothelial wall and exit circulation.
    • Splenic sequestration and destruction
    • Adherence to the vascular endothelium
  3. Accelerated peripheral destruction[3]

Causes

Agranulocytosis is most commonly attributed to malignancy and idiosyncratic drug reactions.

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.

More than 125 drugs have been identified as causative agents of agranulocytosis. The following medications account for over 50% of definitive cases: antiepileptics, antithyroid drugs (carbimazole, methimazole, propylthiouracil), antibiotics (penicillin, chloramphenicol, co-trimoxazole, dapsone), cytotoxic chemotherapeutics, arsenic, gold, NSAIDs (indomethacin, naproxen, phenylbutazone, metamizole), antihelminths (mebendazole, albendazole), allopurinol, mirtazapine, and the antipsychotic clozapine.[4][5][6]

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, agranulocytosis can develop in the setting of large granular lymphocyte (LGL) leukemia or Felty's syndrome.[7]

Causes by Organ System

Cardiovascular No underlying causes
Chemical / poisoning Arsenic trioxide, gold salts, strontium-89
Dermatologic Chediak-Higashi disease, dyskeratosis congenita, x-linked, Elejalde syndrome , reticular dysgenesis, reticular dysplasia
Drug Side Effect 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, Diethylpropiondiflunisal, 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

Ear Nose Throat No underlying causes
Endocrine Hyperthyroidism
Environmental No underlying causes
Gastroenterologic Glycogen storage disorder, hypersplenism, Shwachman-Diamond syndrome
Genetic Barth syndrome, cartilage-hair hypoplasia, Chediak-Higashi disease, Cohen syndrome, Dubowitz syndrome, Elejalde syndrome , familial histiocytic reticulosis, Fanconi syndrome, fumarate hydratase deficiency, Griscelli syndrome type 1, methylmalonic aciduria, myelokathexis, propionic acidemia, propionyl-CoA carboxylase deficiency PCCA type, Shwachman-Diamond syndrome, WHIM syndrome
Hematologic Alloimmune neonatal neutropenia, alloimmune neutropenia in infancy, aplastic anemia, 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
Iatrogenic Hemodialysis, radiation therapy
Infectious Disease Brucellosis, cytomegalovirus, dengue, Epstein-Barr virus, hepatitis A, hepatitis B, hepatitis C, hepatitis, human granulocytic ehrlichiosis, human immunodeficiency virus, 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
Musculoskeletal / Ortho Cartilage-hair hypoplasia, metaphyseal chondrodysplasia, Mckusick type
Neurologic Fumarate hydratase deficiency
Nutritional / Metabolic Copper deficiency, glutathione synthase deficiency, glycogen storage disorder, glycogenosis type 1b, hereditary orotic aciduria, isovaleric acidemia, methylmalonic aciduria, propionic acidemia, propionyl-CoA carboxylase deficiency PCCA type, vitamin deficiencies
Obstetric/Gynecologic No underlying causes
Oncologic Chronic lymphocytic leukemia, hairy cell leukemia, histiocytosis X, leukemia, myelodysplastic syndrome, myelofibrosis
Opthalmologic No underlying causes
Overdose / Toxicity Alcoholism
Psychiatric No underlying causes
Pulmonary Severe acute respiratory syndrome
Renal / Electrolyte Fanconi syndrome
Rheum / Immune / Allergy Alloimmune neonatal neutropenia, alloimmune neutropenia in infancy, autoimmune lymphoproliferative syndrome type 1, autoimmune lymphoproliferative syndrome type 2, autoimmune neutropenia, common variable immune deficiency, Felty's syndrome, histiocytosis X, hyper-immunoglobulin M syndrome, lupus, rheumatoid arthritis, secondary autoimmune neutropenia, WHIM syndrome, x-linked agammaglobulinemia, x-linked hyperimmunoglobulin M syndrome
Sexual No underlying causes
Trauma No underlying causes
Urologic No underlying causes
Dental No underlying causes
Miscellaneous No underlying causes

Differentiating [Disease] 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 these patients can deteriorate rapidly without appropriate treatment.

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.[8]
  • 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.
  • Autoimmune: Antibody-mediated neutrophil destruction.[7]

Epidemiology and Demographics

Neutropenia is typically identified in at-risk patients undergoing cytotoxic chemotherapy or on other myelosuppressive medications. While some ethnicities have an unusually high prevalence of asymptomatic mild neutropenia (ANC 1,000-1500 cells/microliter) known as constitutional or benign ethnic neutropenia (BEN), these do not progress to agranulocytosis, do not increase the risk of infection, and present no additional risk in the setting of cytotoxic chemotherapy as these individuals have normal bone marrow neutrophil reserves.[9][10][11].

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's syndrome.[7]

Risk Factors

Screening

Natural History, Complications, and Prognosis

Natural History

Complications

Prognosis

Diagnosis

Diagnostic Criteria

The diagnosis is made after a complete blood count, a routine blood test. The absolute neutrophil count in this test will be below 500, and can reach 0 cells/mm³. Other kinds of blood cells are typically present in normal numbers.

To formally diagnose agranulocytosis, other pathologies with a similar presentation must be excluded, such as aplastic anemia, paroxysmal nocturnal hemoglobinuria, myelodysplasia and leukemias. This requires a bone marrow examination that shows normocellular (normal amounts and types of cells) blood marrow with underdeveloped promyelocytes. These underdeveloped promyelocytes, if fully matured, would have been the missing granulocytes.

History and Symptoms

Physical Examination

Agranulocytosis may be asymptomatic, or may clinically present with sudden fever, rigors and sore throat. Infection of any organ may be rapidly progressive (e.g., pneumonia, urinary tract infection). Septicemia may also progress rapidly.

Laboratory Findings

Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

In patients that have no symptoms of infection, management consists of close monitoring with serial blood counts, withdrawal of the offending agent (e.g., medication), and general advice on the significance of fever.

Transfusion of granulocytes would have been a solution to the problem. However, granulocytes live only ~10 hours in the circulation (for days in spleen or other tissue), which gives a very short-lasting effect. In addition, there are many complications of such a procedure.

Surgery

There are no surgical treatments for agranulocytosis. In patients' with neutropenic fever, surgical intervention may be necessary depending on the source of infection.

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 G-CSF (granulocyte-colony stimulating factor) can be considered to speed myeloid reconstitution.

See also

References

  1. Dameshek W. (1944). "Leukopenia and Agranulocytosis". Oxford University Press. 1: 841–52. Text "NLM ID 39120200R" ignored (help)
  2. 2.0 2.1 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)
  3. Kumar, Vinay (2007). Robbins Basic Pathology (8 ed.). 441: Elsevier.
  4. Elisa Mari; Franco Ricci; Davide Imberti; Massimo Gallerani (June 2011). "Agranulocytosis: an adverse effect of allopurinol treatment". Italian Journal of Medicine. 5 (2): 120–3. doi:10.1016/j.itjm.2011.02.006.
  5. Diaz, Jaime (1996). How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall. ISBN 0132815605.
  6. Andersohn F, Konzen C, Garbe E (May 2007). "Systematic review: agranulocytosis induced by nonchemotherapy drugs". Ann. Intern. Med. 146 (9): 657–65. doi:10.7326/0003-4819-146-9-200705010-00009. PMID 17470834.
  7. 7.0 7.1 7.2 Bucknall RC, Davis P, Bacon PA, Jones JV (2009). "Neutropenia in rheumatoid arthritis: studies on possible contributing factors". Ann Rheum Dis. 41 (3): 242–7. PMID 6979979.
  8. Andersohn F, Konzen C, Garbe E (May 2007). "Systematic review: agranulocytosis induced by nonchemotherapy drugs". Ann. Intern. Med. 146 (9): 657–65. doi:10.7326/0003-4819-146-9-200705010-00009. PMID 17470834.
  9. Shoenfeld Y, Alkan ML, Asaly A, Carmeli Y, Katz M (1988). "Benign familial leukopenia and neutropenia in different ethnic groups". Eur J Haematol. 41 (3): 273–7. PMID 3181399.
  10. Shoenfeld Y, Ben-Tal O, Berliner S, Pinkhas J (1985). "The outcome of bacterial infection in subjects with benign familial leukopenia (BFL)". Biomed Pharmacother. 39 (1): 23–6. PMID 4027348.
  11. Hsieh MM, Tisdale JF, Rodgers GP, Young NS, Trimble EL, Little RF (2009). "Neutrophil count in African Americans: lowering the target cutoff to initiate or resume chemotherapy?". J Clin Oncol. 28 (10): 1633–7. PMID 20194862.

Template:WS Template:WH