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    Agranulocytosis (Agranulocytoses)

    Agranulocytosis is a condition which is characterized by decrease in the neutrophil count below 100/mL of blood. These blood cells play a key role in the elimination of pathogens.

    Presentation

    Initial signs and symptoms of agranulocytosis include onset of sudden fever accompanied by chills with development of weakness in hands and legs. In addition to these, there is development of sores in the mouth, throat. In severe cases ulcers are also known to develop and which can lead to bleeding. Affected individuals can also experience rapid breathing, development of skin abscesses, rapid heart rate and a sudden drop in blood pressure [8].

    gastrointestinal
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  • Entire body system
    Fever
    • Utilization of neutrophils can occur in infections [3] Signs and symptoms [ edit ] Agranulocytosis may be asymptomatic , or may clinically present with sudden fever, rigors and sore throat.[en.wikipedia.org]
    • Treatments for persistent bacterial infection with fever include amphotericin B or corticosteroid therapy.[primeinc.org]
    • Prevailing low grade fever may progress into a high fever or hypothermia along with rapid breathing, confusion, and body swelling.[explainmedicine.com]
    • An acute disease characterized by high fever, lesions of the mucous membranes and skin, and a sharp drop in circulating granular white blood cells.[dictionary.reference.com]
    • Clinical findings Fever, malaise, mucocutaneous ulcers (throat, GI tract, skin). agranulocytosis Granulocytopenia, granulopenia Hematology A marked in PMNs 500/mm3 Clinical Fever, malaise, mucocutaneous ulcers–throat, GI tract, skin Etiology Acquired[medical-dictionary.thefreedictionary.com]
    Chills
    • , malaise, sore throat, fever, chills, muscle aches, headache, and swollen neck Cocaine/Snort 1 0 5/31/09 7 Not done Full recovery 16 Washington 40s Female Unknown Acute febrile illness with pharyngitis Crack/Smoke Powder/Snort 0 0 6/05/09 2 Not done[cdc.gov]
    • Initially patients may be asymptomatic or may present with malaise, fever with or without chills, marked weakness and fatigue.[explainmedicine.com]
    • The first manifestations are usually produced by a severe infection and include high fever, chills, prostration, and ulcerations of mucous membranes such as in the mouth, rectum, or vagina.[medical-dictionary.thefreedictionary.com]
    • […] myelodysplasia) Chemotherapy Bone marrow transplantation Cancer Blood transfusions Nutritional deficiencies Medications such as rituximab, penicillin, captopril, and ranitidine Agranulocytosis Symptoms Common symptoms of agranulocytosis include sudden fever, chills[stlouischildrens.org]
    • Origin and Etymology of agranulocytosis Medical Dictionary plural agranulocytoses play \ -ˌsēz \ : an acute blood disorder that is marked by a decrease of circulating granulocytes (such as neutrophils) and is characterized especially by weakness, chills[merriam-webster.com]
    Rigor
    • Utilization of neutrophils can occur in infections [3] Signs and symptoms [ edit ] Agranulocytosis may be asymptomatic , or may clinically present with sudden fever, rigors and sore throat.[en.wikipedia.org]
    • URAC's accreditation program is an independent audit to verify that A.D.A.M. follows rigorous standards of quality and accountability.[scripps.org]
    • […] note that without medical intervention, in particular immediate antibiotic administration, most elderly patients ( 60% in our experience) develop severe and potentially life-threatening infections with signs of general sepsis and septicemia (fever, rigor[esciencecentral.org]
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  • Jaw & Teeth
    Sore Mouth
    • The early symptoms of agranulocytosis may include: sudden fever chills sore throat weakness in your limbs sore mouth and gums mouth ulcers bleeding gums Other signs and symptoms of agranulocytosis can include: fast heart rate rapid breathing low blood[healthline.com]
    • If you use cocaine, watch out for: high fever, chills, or weakness, swollen glands, painful sores (mouth, anal), any infection that won't go away or gets worse very fast, including sore throat or mouth sores, skin infections, abscesses, thrush (white[dmd.aspetjournals.org]
    Bleeding Gums
    • The early symptoms of agranulocytosis may include: sudden fever chills sore throat weakness in your limbs sore mouth and gums mouth ulcers bleeding gums Other signs and symptoms of agranulocytosis can include: fast heart rate rapid breathing low blood[healthline.com]
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  • Workup

    A routine blood test to determine complete blood count is performed at the preliminary level. Complete blood count would reveal neutrophil count below 500 or can even reach 0 cells/mm3. Urine samples would also be checked for signs of infections and count of white blood cells. If bone marrow diseases are the underlying cause, then a sample from bone marrow will be analyzed. In addition to these, various tests would be employed for determining autoimmune diseases. If the agranulocytosis is inherited, then genetic testing would also follow [9].

    Long bone radiographs are suggested if congenital agranulocytosis is suspected. If the patient appears febrile, then chest radiographs would also be required when signs of pneumonia are evident. Along with these, ultrasonography and CT scan would be done to evaluate splenomegaly [10].

    Pathology

    Biopsy
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  • Laboratory

    Serum
    Leukopenia
    • Laboratory tests reveal a profound leukopenia (low leukocyte count).[medical-dictionary.thefreedictionary.com]
    • Agranulocytosis , also known as agranulosis or granulopenia , is an acute condition involving a severe and dangerous leukopenia (lowered white blood cell count), most commonly of neutrophils causing a neutropenia in the circulating blood. [1] [2] It is[en.wikipedia.org]
    • D72.819 ICD-10-CM Diagnosis Code D72.819 Decreased white blood cell count, unspecified 2016 2017 2018 Billable/Specific Code Applicable To Decreased leukocytes, unspecified Leukocytopenia, unspecified Leukopenia Type 1 Excludes malignant leukopenia ([icd10data.com]
    • Etymology [ edit ] a- ‎ granulocyte ‎ -osis Noun [ edit ] agranulocytosis ( countable and uncountable , plural agranulocytoses ) Wikipedia has an article on: agranulocytosis Wikipedia ( medicine ) An acute condition involving a severe and dangerous leukopenia[en.wiktionary.org]
    • 1. a serious, acute blood disease, sometimes related to drug or radiation therapy, characterized by extreme leukopenia, fever, and ulcerations of the mucous membranes.[dictionary.reference.com]
  • more...
  • Treatment

    Treatment of the underlying disease conditions would be the primary requirement. Following this, the symptoms of agranulocytosis would be managed with medications and other therapies. If the patient is suffering from drug-induced agranulocytosis, then the drug which is cause of the problem will be withdrawn and a substitute drug would then be suggested. Antibiotics or antifungal medications would be given for correcting infections.

    Colony stimulating factor therapy is suggested for those individuals who have developed agranulocytosis due to chemotherapy treatment in the past. Granulocyte transfusion is the treatment of choice in cases when the individual has suffered gram negative sepsis and no considerable improvement has been noticed within 24 to 48 hours of initiation of other treatment methods [11].

    Prognosis

    Prognosis largely depends on the etiology and the severity of the disease. Mortality is high in patients who suffer from severe agranulocytosis. Death occurs due to uncontrolled sepsis, which is a secondary accompaniment of the condition. With prompt initiation of treatment, prognosis is good with a significant reduction in mortality rate. When agranulocytosis occurs as a secondary complication to viral infections, then such patients have a good prognosis [7].

    Complications

    Fever
    • Utilization of neutrophils can occur in infections [3] Signs and symptoms [ edit ] Agranulocytosis may be asymptomatic , or may clinically present with sudden fever, rigors and sore throat.[en.wikipedia.org]
    • Treatments for persistent bacterial infection with fever include amphotericin B or corticosteroid therapy.[primeinc.org]
    • Prevailing low grade fever may progress into a high fever or hypothermia along with rapid breathing, confusion, and body swelling.[explainmedicine.com]
    • An acute disease characterized by high fever, lesions of the mucous membranes and skin, and a sharp drop in circulating granular white blood cells.[dictionary.reference.com]
    • Clinical findings Fever, malaise, mucocutaneous ulcers (throat, GI tract, skin). agranulocytosis Granulocytopenia, granulopenia Hematology A marked in PMNs 500/mm3 Clinical Fever, malaise, mucocutaneous ulcers–throat, GI tract, skin Etiology Acquired[medical-dictionary.thefreedictionary.com]
    Shock
    • (e.g. pneumonia), septicemia and septic shock in approximately two-thirds of cases.[esciencecentral.org]
    • Hypotension and signs of septic shock if infection has been present Painful aphthous ulcers [ulcerations on the mucous membranes] may be found in the oral cavity.[cchrflorida.org]
    • […] haemorrhoids - S Slawik, N Kenefick, GL Greenslade - Colorectal , 2007 - Wiley Online Library Of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock[symptoma.com]
    • Evidence exists to implicate both the major histocompatibility complex antigens and heat shock protein variants in determining individual susceptibility, although more patients of different ethnic backgrounds need to be studied.[link.springer.com]
    Stomatitis
    • Stomatitis, gingivitis, perirectal inflammation, colitis, sinusitis, paronychia, and otitis media often occur.[merckmanuals.com]
    Leukopenia
    • Laboratory tests reveal a profound leukopenia (low leukocyte count).[medical-dictionary.thefreedictionary.com]
    • Agranulocytosis , also known as agranulosis or granulopenia , is an acute condition involving a severe and dangerous leukopenia (lowered white blood cell count), most commonly of neutrophils causing a neutropenia in the circulating blood. [1] [2] It is[en.wikipedia.org]
    • D72.819 ICD-10-CM Diagnosis Code D72.819 Decreased white blood cell count, unspecified 2016 2017 2018 Billable/Specific Code Applicable To Decreased leukocytes, unspecified Leukocytopenia, unspecified Leukopenia Type 1 Excludes malignant leukopenia ([icd10data.com]
    • Etymology [ edit ] a- ‎ granulocyte ‎ -osis Noun [ edit ] agranulocytosis ( countable and uncountable , plural agranulocytoses ) Wikipedia has an article on: agranulocytosis Wikipedia ( medicine ) An acute condition involving a severe and dangerous leukopenia[en.wiktionary.org]
    • 1. a serious, acute blood disease, sometimes related to drug or radiation therapy, characterized by extreme leukopenia, fever, and ulcerations of the mucous membranes.[dictionary.reference.com]
    Pneumocystis Carinii Pneumonia
    • carinii pneumonia prophylaxis in HIV negative patients with primary CNS lymphoma - BS Mathew, SA Grossman - Cancer treatment reviews, 2003 - Elsevier Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections - WH Sheng, CC Hung[symptoma.com]
    Agranulocytic Angina
    • Agranulocytosis , also called agranulocytic angina , acute infection characterized by severe sore throat , fever, and fatigue and associated with an extreme reduction of white blood cells, or leukocytes (a condition known as leukopenia ), particularly[britannica.com]
    • Synonyms Agranulocytic Angina Granulocytopenia, Primary Neutropenia , Malignant Disorder Subdivisions None General Discussion Acquired agranulocytosis is a rare, drug-induced blood disorder that is characterized by a severe reduction in the number of[webmd.com]
    • Aalso called agranulocytic angina or granulocytopenia. agranulocytosis pronounced leukopenia (especially circulating polymorpho- nuclear leukocytes), e.g. due to chemotherapy or radiotherapy a·gran·u·lo·cy·to·sis ( ā'gran'yŭ-lō-sī-tō'sis ) An acute potentially[medical-dictionary.thefreedictionary.com]
    • Semin Hematol 2:338–346 Google Scholar Madison FW, Squier TL (1934) The etiology of primary granulocytopenia (agranulocytic angina).[link.springer.com]

    Etiology

    Congenital agranulocytosis is a result of genetic abnormalities present at birth. In such cases, a family history of the disease is evident and therefore, children are likely to develop genetic anomalies which in turn favor decreased neutrophils content in blood.

    The acquired form occurs due to the following factors [2]:

    • Cancer treatment such as radiation and chemotherapy
    • Nutritional deficiencies
    • Cancer affecting the bone marrow
    • Various drugs such as clozapine [3]
    • Infections
    • Autoimmune diseases like systemic lupus erythematosus
    • Exposure to chemicals such as DDT

    A recent outbreak of agranulocytosis was reported amongst cocaine users in the period of 2008 – 2009 in the US and Canada by the Center for Disease Control and Prevention [4]. Such a type of trend suggests a strong link between use of cocaine and development of agranulocytosis.

    Epidemiology

    The exact incidence of agranulocytosis is unknown. From the available data, it can be estimated that the condition occurs in 1 – 3.4 cases per million every year. For the drug induced variety, 1 case is reported to occur per million individuals each year.

    Women are more prone to develop the condition compared to males; the reason being that females consume more medications. Agranulocytosis has predilection for the Black race and is a common phenomenon amongst those population [5].

    Sex distribution
    Age distribution

    Pathophysiology

    Under normal conditions there are approximately 1500 granulocytes/ml of blood. Granulocytes are originally comprised of 3 types of cells; namely neutrophils, lymphocytes and monocytes. Amongst these, neutrophils make up for the larger share and play a major role in preventing the body against infections and helps in building immunity.

    The mature forms of neutrophils are made by precursors in the bone marrow. Once the neutrophils mature and leave the bone marrow, they enter the blood without re-entering the bone marrow. Factors or conditions that interfere with production of mature neutrophils in the bone marrow give rise to the condition of agranulocytosis [6].

    Prevention

    Agranulocytosis cannot always be prevented. However, if drugs are the cause, then withdrawing the drugs can also help prevent its onset. Use of prophylactic antibiotics can go a long way in preventing the condition [12].

    Summary

    Agranulocytosis can either be acquired or may be present from birth – congenital. In the acquired type, the bone marrow is unable to produce stem cells that eventually mature into granulocytes. Or it may so happen that the granulocytes are destroyed faster than normal. In the congenital agranulocytosis, there is some kind of genetic defect that is present from birth. Affected individuals are highly susceptible to infections due to severely suppressed immune system [1].

    Patient Information

    Definition: Agranulocytosis is a condition, characterized by very low levels of neutrophil count in blood. Such individuals are frequently prone to contract infections due to compromised immunity.

    Cause: Underlying disease conditions such as bone marrow diseases, autoimmune disorders and cancer, pave way for development of agranulocytosis. Other factors that causes the neutrophils count to fall too low include genetic defects, poor nutrition, drugs and therapies employed for cancer treatment.

    Symptoms: Symptoms include fever, chills, infections and sore throat. Affected individuals can also develop mouth ulcers which in severe cases can even bleed. Infections of organ can develop and progress at a rapid rate.

    Diagnosis: A preliminary complete blood profile to determine the neutrophil count is carried out. In addition, urine analysis would also be done to determine infections. Imaging studies such as radiographs and CT scan are indicated in cases, when there is infection of lungs and congenital agranulocytosis is suspected. Long bone radiographs are required in cases when the patient appears febrile.

    Treatment: Treatment is geared towards correcting the underlying condition that is causing the problem. In addition, antibiotics or antiviral agents are administered if infections have set in. If drugs are the offending agents, then these are withdrawn and replaced with a substitute.

    Self-assessment

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    References

    1. Young NS. Agranulocytosis. JAMA 1994; 271:935.
    2. Kaufman DW, Kelly JP, Jurgelon JM, et al. Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol Suppl 1996; 60:23.
    3. Alvir JM, Lieberman JA, Safferman AZ, et al. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med 1993; 329:162.
    4. Zhu NY, Legatt DF, Turner AR. Agranulocytosis after consumption of cocaine adulterated with levamisole. Ann Intern Med 2009; 150:287.
    5. Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe's Clinical Hematology. Vol 2. 10th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:1862-82.
    6. Watts RG. Neutropenia. In: Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe's Clinical Hematology. 10thed. Baltimore, Md: Lippincott, Williams & Wilkins; 1999:1862-1888.
    7. Pathak R, Giri S, Aryal MR, Karmacharya P, Bhatt VR, Martin MG. Mortality, length of stay, and health care costs of febrile neutropenia-related hospitalizations among patients with breast cancer in the United States. Support Care Cancer. Jan 4 2015
    8. Gerson SL, Meltzer H. Mechanisms of clozapine-induced agranulocytosis. Drug Saf 1992; 7 Suppl 1:17.
    9. Xia J, Bolyard AA, Rodger E, Stein S, Aprikyan AA, Dale DC, et al. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. Br J Haematol. Nov 2009;147(4):535-42
    10. Donadieu J, Fenneteau O, Beaupain B, et al. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis 2011; 6:26.
    11. Massey E, Paulus U, Doree C, Stanworth S. Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. Jan 21 2009;CD005341.
    12. Cullen M, Baijal S. Prevention of febrile neutropenia: use of prophylactic antibiotics. Br J Cancer. Sep 2009;101 Suppl 1:S11-4.

    • Antibiotic-induced agranulocytosis: a monocentric study of 21 cases - E Andres, F Maloisel - Archives of internal medicine, 2001 - Am Med Assoc
    • Colon ulceration and perforation in cyclic neutropenia - GW Geelhoed, MA Kane, DC Dale, SA Wells - Journal of pediatric surgery, 1973 - Elsevier
    • Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections - WH Sheng, CC Hung, YC Chen, CT Fang, SM Hsieh - Qjm, 1999 - Oxford Univ Press
    • Agranulocytosis and systemic candidiasis following clomipramine therapy - RL Souhami, CR Ashton, JP Lee-Potter - Postgraduate medical journal, 1976 - pmj.bmj.com
    • [Stomatitis in childhood, not always benign] - AM Oudshoorn, C Ramaker - Nederlands tijdschrift voor , 2000 - ukpmc.ac.uk
    • A review of the complications of burns, their origin and importance for illness and death - S Sevitt - J Trauma, 1979 - ukpmc.ac.uk
    • A recalcitrant, erythematous, desquamating disorder associated with toxin-producing staphylococci in patients with AIDS - LA Cone, DR Woodard, RG Byrd - Journal of Infectious , 1992 - jid.oxfordjournals.org
    • A review of fifty-one cases of multiple myeloma: emphasis on pneumonia and other infections as complications - H GLENCHUR, HH ZINNEMAN - Archives of Internal , 1959 - Am Med Assoc
    • A prospective evaluation of stapled haemorrhoidopexy/rectal mucosectomy in the management of 3rd and 4th degree haemorrhoids - S Slawik, N Kenefick, GL Greenslade - Colorectal , 2007 - Wiley Online Library
    • Agranulocytosis - WH GORDON - Annals of Internal Medicine, 1930 - Am Coll Physicians
    • A coincidence of disastrous accidents: Crohn's disease, agranulocytosis, and Clostridium septicum infection - F Thalhammer, U Hollenstein, K Janata - The Journal of , 1997 - journals.lww.com
    • Aspergillosis case-fatality rate: systematic review of the literature - SJ Lin, J Schranz, SM Teutsch - Clinical Infectious Diseases, 2001 - cid.oxfordjournals.org
    • Pneumocystis carinii pneumonia prophylaxis in HIV negative patients with primary CNS lymphoma - BS Mathew, SA Grossman - Cancer treatment reviews, 2003 - Elsevier
    • Fatal Legionella pneumonitis in a neutropenic leukemic child. - MF Gutzeit, SJ Lauer, WM Dunne Jr - infectious disease , 1987 - ncbi.nlm.nih.gov
    • Agranulocytosis - G Bewley, SV Furlong - Irish Journal of Medical Science (1926-1967), 1937 - Springer
    • Of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock* - MWA Angstwurm, L Engelmann - Critical care , 2007 - journals.lww.com
    • Agranulocytosis in a Mother and her Young Daughter, the Possible Role of Genetic Factors in the Development of Methimazole-Induced Agranulocytosis - A Bahrami - International Journal of Endocrinology and , 2012 - endometabol.com
    • Agranulocytosis and antithyroid drugs - MH Rosove - Western Journal of Medicine, 1977 - ncbi.nlm.nih.gov
    • Agranulocytosis from Tripelennamine (Pyribenzamine®) Hydrochloride - AW Hilker - Journal of the American Medical Association, 1950 - Am Med Assoc
    • Clozapine-induced agranulocytosis--incidence and risk factors in the United States - JMJ Alvir, JA Lieberman, AZ Safferman - England Journal of , 1993 - Mass Medical Soc
    • Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections - WH Sheng, CC Hung, YC Chen, CT Fang, SM Hsieh - Qjm, 1999 - Oxford Univ Press

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