Agranulocytosis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2] 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
- Kostmann's syndrome
- Reticular dysgenesis
- Shwachman-Diamond syndrome
- Chediak-Higashi syndrome
- Dyskeratosis congenita
Acquired
- Drug induced
- Infection
- Collagen vascular diseases
- White cell aplasia
- Nutritional deficiency
- Myelodysplasia
- Hypoplasia
- Leukemia
Pathophysiology
Agranulocytosis develops as a result of the following mechanisms:[2]
- Immune mediated destruction of granulocytes
- The drugs or its active metabolite act as hapten, and binds to neutrophil membrane.
- Autoantibodies are produced as a result of this binding.
- This results in destruction of sensitized neutrophils by phagocytosis.
- Most common drugs are propylthiouracil, amodiaquine, mono-desethyl amodiaquine, and flecainide.
- Direct damage of granulocytes
- Some drugs release chemically active metabolites.
- These metabolites bind to cytoplasmic proteins or proteins in the nucleus.
- This results in direct toxicity and destruction of granulocytes.
- Chlorpromazine, dapsone, clozapine, and procainamide are few examples of these drugs.
- Granulocytes oxidize clozapine releasing nitrenium ions.[3]
- Nitrenium ions bind irreversibly to granulocytes and its precursor cells resulting in toxic destruction of these cells.
Causes
Agranulocytosis can be congenital or acquired. Common causes of acquired agranulocytosis include:[4][5]
- Medications
- Chemotherapy
- Bone marrow transplant
- Systemic lupus erythematosus (SLE)
- Rheumatoid arthritis
- HIV
- Hepatitis
- Leukemia
- Myelodysplasia
Differentiating Agranulocytosis from Other Diseases
Consider the following differential when evaluating a patient with agranulocytosis:
- Bacterial sepsis
- Aplastic anemia
- Acute myeloid leukemia
- Acute lymphoblastic leukemia
- Cytomegalovirus
- Folic acid deficiency
- Hodgkin lymphoma
- Non-Hodgkin lymphoma
- Wegener granulomatosis
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:
- Acquired conditions
- Medications[8]
- Infectious mononucleosis[9]
- Combination therapy with ACE inhibitors and interferon[10]
- Cytotoxic chemotherapy
- Hematologic malignancies
- Autoimmune disorders
- Genetic susceptibility
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
- Neutropenia, and progression to agranulocytosis, occurs in either a dose-dependent or 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 idiosyncratic, and immune-mediated neutropenia that occurs independently.
Complications
The major complications of agranulocytosis are as follows:[14]
Prognosis
The negative prognostic factors for agranulocytosis are:[15]
- Neutrophil count at the time of diagnosis <0.1 × 109 cells/L
- Age > 65 years old
- Severe infections like septic shock, bacteremia
- Pre existence of systemic infections, renal, cardiac and respiratory diseases
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]
- Fever
- Symptoms of frequent infections
- Unusual redness, pain, or swelling around a wound
- Mouth ulcers
- Diarrhea
- Burning sensation when urinating
- Sore throat
- Shortness of breath
- Shaking chills
Physical Examination
Common signs of agranulocytosis may include:
- Fever
- Tachycardia
- Hypotension
- Tachypnea
- Hypoxia
- Jaundice
- Wheezes
- Rales
- Joint swelling or deformity
- Rashes
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 blood flow cytometry
- Antinuclear antibody (ANA)
- 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
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.
- Treat the associated infections and conditions
- In cases of febrile neutropenia, empiric antibiotics should be administered intravenously as early as possible.[17]
- Before starting the antibiotics, blood, urine and sputum cultures should be withdrawn.
- Antibiotic coverage should be bactericidal for most common pathogens.[18][19][20]
- Central venous catheters and other indwelling devices should be removed when possible if there is suspicion for infection or with positive blood cultures.
- Use of granulocyte-colony stimulating factor
- Granulocyte-colony stimulating factor (G-CSF) has shown excellent results in patients with drug induced agranulocytosis and severe infection.[16]
- It is mostly beneficial in patients with neutropenia secondary to chemotherapy.
- Immune suppression
- In neutropenia with autoimmune diseases, prednisone is used for immunosuppression.
- 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:
- Avoiding certain medications
- 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.
Secondary Prevention
Effective measures for the secondary prevention of agranulocytosis include early detection and treatment of underlying conditions.
See also
References
- ↑ Dameshek W. (1944). "Leukopenia and Agranulocytosis". Oxford University Press. 1: 841–52. Text "NLM ID 39120200R" ignored (help)
- ↑ 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.
- ↑ 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.
- ↑ 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)
- ↑ 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.
- ↑ Strom, Brian L. (1992). "Descriptive Epidemiology of Agranulocytosis". Archives of Internal Medicine. 152 (7): 1475. doi:10.1001/archinte.1992.00400190095018. ISSN 0003-9926.
- ↑ 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.
- ↑ 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)
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 13.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 16.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.