History

Fact Explanation
Non specific symptoms related to an infection Acute onset severe reduction of granulocytes (mainly neutrophils) in peripheral blood smear below 500/µL is called as agranulocytosis. This is also known as severe neutropenia. (Mild neutropenia - 1000-2000/µL, Moderate neutropenia - 500-1000/µL) Acute reduction can be due to several causes. Ineffective granulopoiesis (Suppression of hematopoietic stem cells like in Aplastic anemia) or accelerated removal or destruction of neutrophils (Immune mediated/ idiopathic/ autoimmune/ drugs splenic sequestration secondary to enlargement of spleen/ increased peripheral utilization in an overwhelming infection) are the major causes. [1,2,3,4] Reduction of neutrophil count may increase the risk of infection due to declined immunity. Initially patients may be asymptomatic or may present with malaise, fever with or without chills, marked weakness and fatigue. All these symptoms are acute in onset. [1,2,5,6,7]
Soar throat Later in the course of the disease, patient develops more specific infections. Pharyngitis is one of the most common. It manifests as sore throat or a tickling throat sensation. Some patients may complain of odynophagia or dysphagia as well. [1,2,3,4,5]
Recurrent sinusitis Sinusitis is another common infection that occurs in agranulocytosis. Patients may have headache, nasal congestion and discharge. [1,2,3,5,6]
Skin infection Skin is another site that more prone to infections. This may results in rashes, ulcers or abscesses.[2,3,5,6]
Gum bleeding and swelling Patients commonly develop periodontitis. They may present with redness or bleeding of gums specially while brushing teeth, recurrent gum swelling and halitosis (bad breath). [4,5,6]
Difficulty in breathing Patients may occasionally develop bacterial pneumonia and present with shortness of breath, productive cough, fever with chills, sharp or stabbing chest pain during deep breaths. Pneumonias may rarely fungal in origin. [2,5,6]
Septicemia Patients are more prone to overwhelming infections which may rapidly progress into a life threatening sepsis. Prevailing low grade fever may progress into a high fever or hypothermia along with rapid breathing, confusion, and body swelling. Urine output may decrease as well. [1,2,3,4,5]
Risk factors Patients who are undergoing chemotherapy treatment, taking certain drugs and getting exposed to certain chemical toxins or radiation are at risk of developing agranulocytosis. [1,2,3,4,7,8]
Drug history The most common cause of agranulocytosis is drug toxicity. Alkylating drugs and antimetabolite drugs that cause generalized suppression of bone marrow. This effect is dose related and hence predictable. Drugs such as chlorpromazine and phenothiazines have a toxic effect on granulocytic precursors in bone marrow whereas thiouracil, sulfonamides and aminopyrine trigger an antibody mediated destruction of mature neutrophils. [1,2,3,4,5]
Family history of infections or sudden death Agranulocytosis may have a genetic basis. Neutropenia is more common in black races. Kostmann's syndrome is characterized by inherited severe infantile agranulocytosis Shwachman-Diamond syndrome and Dyskeratosis congenita are some other familial causes of agranulocytosis. [1,2,3]
References
  1. MARCUS RE, GOLDMAN JM. Management of infection in the neutropenic patient. Br Med J (Clin Res Ed) [online] 1986 Aug 16, 293(6544):406-8 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/3091137
  2. SAMMUT SJ, MAZHAR D. Management of febrile neutropenia in an acute oncology service. QJM [online] 2012 Apr, 105(4):327-36 [viewed 12 July 2014] Available from: doi:10.1093/qjmed/hcr217
  3. JAMES RM, KINSEY SE. The investigation and management of chronic neutropenia in children. Arch Dis Child [online] 2006 Oct, 91(10):852-8 [viewed 12 July 2014] Available from: doi:10.1136/adc.2006.094706
  4. MANDELL LA. Management of the febrile neutropenic patient. Can Med Assoc J [online] 1983 Apr 15, 128(8):915-7 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/6831337
  5. KRELL D, JONES AL. Impact of effective prevention and management of febrile neutropenia Br J Cancer [online] 2009 Sep, 101(Suppl 1):S23-S26 [viewed 12 July 2014] Available from: doi:10.1038/sj.bjc.6605273
  6. WRIGHT JD, NEUGUT AI, ANANTH CV, LEWIN SN, WILDE ET, LU YS, HERZOG TJ, HERSHMAN DL. Deviations from guideline-based therapy for febrile neutropenia in cancer patients and their effect on outcomes. JAMA Intern Med [online] 2013 Apr 8, 173(7):559-68 [viewed 12 July 2014] Available from: doi:10.1001/jamainternmed.2013.2921
  7. KRZEMIENIECKI K, SEVELDA P, ERDKAMP F, SMAKAL M, SCHWENKGLENKS M, PUERTAS J, TROJAN A, SZABO Z, BENDALL K, MAENPAA J. Neutropenia management and granulocyte colony-stimulating factor use in patients with solid tumours receiving myelotoxic chemotherapy--findings from clinical practice. Support Care Cancer [online] 2014 Mar, 22(3):667-77 [viewed 12 July 2014] Available from: doi:10.1007/s00520-013-2021-2
  8. CULLEN M, BAIJAL S. Prevention of febrile neutropenia: use of prophylactic antibiotics Br J Cancer [online] 2009 Sep, 101(Suppl 1):S11-S14 [viewed 12 July 2014] Available from: doi:10.1038/sj.bjc.6605270

Examination

Fact Explanation
Fever Patients may present initially with low grade fever. As the disease progress, it may change into a high grade fever with chills and rigors. Hypothermia indicates development of septicemia. [1,2,3,4,5]
Oral mucosal lesions Painful aphthous ulcers, oral thrush or signs of periodontal disease such as gum swelling, erythema, tenderness and gum bleeding are common manifestations in oral mucosal involvement. [2,3,4,5]
Cutaneous infectious foci Skin rashes, ulcers or abscesses are the common skin involvements. [3,4,5,6]
Lymphadenopathy Lymphadenopathy is a possible indication of a disseminated infection. [4,5,6]
Signs of lower respiratory tract infections Fever with tachypnea, mucopurulent sputum and lung crepitations are suggestive of more severe infections like bacterial pneumonia. [1,2,3,7,8]
Splenomegaly Splenomegaly may give a clue regarding the pathogenesis of low granulocyte count. Splenic sequestration of neutrophils may cause splenic enlargement. (eg- Felty's syndrome, leukemia) [1,2,3,5]
Perirectal / perineal lesions Perirectal abscesses or perianal abscess and rashes are suggestive of the involvement of the infections of the respective regions.[1,2,4,6,7]
Signs of septicemia Fever and shaking chills or, alternatively, hypothermia, decreased urination, tachycardia, hypotension, tachypnea, nausea and vomiting are suggestive of development of the septicemia and septic shock. Though this is the more severe form of disease, patient may present with these symptoms. [1,2,5]
References
  1. MANDELL LA. Management of the febrile neutropenic patient. Can Med Assoc J [online] 1983 Apr 15, 128(8):915-7 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/6831337 5) RODRIGUEZ A, YOOD R, CONDON T, FOSTER C. Recurrent uveitis in a patient with adult onset cyclic neutropenia associated with increased large granular lymphocytes Br J Ophthalmol [online] 1997 May, 81(5):415 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1722187
  2. MARCUS RE, GOLDMAN JM. Management of infection in the neutropenic patient. Br Med J (Clin Res Ed) [online] 1986 Aug 16, 293(6544):406-8 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/3091137
  3. SAMMUT SJ, MAZHAR D. Management of febrile neutropenia in an acute oncology service. QJM [online] 2012 Apr, 105(4):327-36 [viewed 12 July 2014] Available from: doi:10.1093/qjmed/hcr217
  4. JAMES RM, KINSEY SE. The investigation and management of chronic neutropenia in children. Arch Dis Child [online] 2006 Oct, 91(10):852-8 [viewed 12 July 2014] Available from: doi:10.1136/adc.2006.094706
  5. WRIGHT JD, NEUGUT AI, ANANTH CV, LEWIN SN, WILDE ET, LU YS, HERZOG TJ, HERSHMAN DL. Deviations from guideline-based therapy for febrile neutropenia in cancer patients and their effect on outcomes. JAMA Intern Med [online] 2013 Apr 8, 173(7):559-68 [viewed 12 July 2014] Available from: doi:10.1001/jamainternmed.2013.2921
  6. KRZEMIENIECKI K, SEVELDA P, ERDKAMP F, SMAKAL M, SCHWENKGLENKS M, PUERTAS J, TROJAN A, SZABO Z, BENDALL K, MAENPAA J. Neutropenia management and granulocyte colony-stimulating factor use in patients with solid tumours receiving myelotoxic chemotherapy--findings from clinical practice. Support Care Cancer [online] 2014 Mar, 22(3):667-77 [viewed 12 July 2014] Available from: doi:10.1007/s00520-013-2021-2
  7. KRELL D, JONES AL. Impact of effective prevention and management of febrile neutropenia Br J Cancer [online] 2009 Sep, 101(Suppl 1):S23-S26 [viewed 12 July 2014] Available from: doi:10.1038/sj.bjc.6605273
  8. CULLEN M, BAIJAL S. Prevention of febrile neutropenia: use of prophylactic antibiotics Br J Cancer [online] 2009 Sep, 101(Suppl 1):S11-S14 [viewed 12 July 2014] Available from: doi:10.1038/sj.bjc.6605270

Differential Diagnoses

Fact Explanation
Leukemia A malignant bone marrow disease in which hematopoietic precursors cells are arrested in an early stage of their development. Symptoms may include bleeding and bruising problems, fatigue, and an increased risk of infections. [1]
Aplastic anemia A syndrome of bone marrow failure which is characterized by pancytopenia of peripheral blood and marrow hypoplasia. The onset is insidious, and the initial symptom is related to anemia or bleeding or infections. [2]
Infectious Mononucleosis Infectious Mononucleosis is an infection usually caused by the Epstein-Barr virus. The virus spreads through saliva. Infectious Mononucleosis is common among adolescents and young adulthood and presents with a characteristic triad, namely, fever , sore throat and lymphadenopathy.[3]
Paroxysmal nocturnal hemoglobinuria Paroxysmal nocturnal hemoglobinuria is a rare, genetically acquired life-threatening disease of the blood characterized by complement-induced intravascular hemolytic anemia, hematuria and thrombosis. [4]
Lymphoma Lymphoma is cancer of the lymphatic system. Symptoms may include painless lymphadenopathy, fevers, night sweats, pruritus, weight loss and fatigability. [5]
Multiple Myeloma A debilitating malignancy which is part of a spectrum ranging from plasma cell leukemia to monoclonal gammopathy of unknown significance. Common presenting symptoms may include bone pain, pathologic fractures, weakness, malaise, bleeding, features of anemia and infections. [6]
Myelodysplasia Myelodysplastic syndromes are a group of disorders caused by poorly formed or dysfunctional blood cells. Weakness, malaise, bleeding, features of anemia and infections are the common presenting features. [7]
References
  1. CREUTZIG U, VAN DEN HEUVEL-EIBRINK MM, GIBSON B, DWORZAK MN, ADACHI S, DE BONT E, HARBOTT J, HASLE H, JOHNSTON D, KINOSHITA A, LEHRNBECHER T, LEVERGER G, MEJSTRIKOVA E, MESHINCHI S, PESSION A, RAIMONDI SC, SUNG L, STARY J, ZWAAN CM, KASPERS GJ, REINHARDT D, AML COMMITTEE OF THE INTERNATIONAL BFM STUDY GROUP. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood [online] 2012 Oct 18, 120(16):3187-205 [viewed 12 July 2014] Available from: doi:10.1182/blood-2012-03-362608
  2. BISWAJIT H, PRATIM PP, KUMAR ST, SHILPI S, KRISHNA GB, ADITI A. Aplastic anemia: a common hematological abnormality among peripheral pancytopenia. N Am J Med Sci [online] 2012 Sep, 4(9):384-8 [viewed 12 July 2014] Available from: doi:10.4103/1947-2714.100980
  3. GONZáLEZ SALDAñA N, MONROY COLíN VA, PIñA RUIZ G, JUáREZ OLGUíN H. Clinical and laboratory characteristics of infectious mononucleosis by Epstein-Barr virus in Mexican children. BMC Res Notes [online] 2012 Jul 20:361 [viewed 12 July 2014] Available from: doi:10.1186/1756-0500-5-361
  4. GREEN H, ELIAKIM-RAZ N, ZIMRA Y, GAFTER-GVILI A. Paroxysmal nocturnal hemoglobinuria diagnosed after influenza vaccine: coincidence or consequence? Isr Med Assoc J [online] 2014 Feb, 16(2):122-4 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24645235
  5. KWAK JY. Treatment of diffuse large B cell lymphoma. Korean J Intern Med [online] 2012 Dec, 27(4):369-77 [viewed 12 July 2014] Available from: doi:10.3904/kjim.2012.27.4.369
  6. ESLICK R, TALAULIKAR D. Multiple myeloma: from diagnosis to treatment. Aust Fam Physician [online] 2013 Oct, 42(10):684-8 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24130968
  7. CAZZOLA M, DELLA PORTA MG, MALCOVATI L. The genetic basis of myelodysplasia and its clinical relevance. Blood [online] 2013 Dec 12, 122(25):4021-34 [viewed 12 July 2014] Available from: doi:10.1182/blood-2013-09-381665

Investigations - for Diagnosis

Fact Explanation
Full blood count Full blood count is the most important investigation in terms of diagnosis. The absolute neutrophil count will be below 500, and can even reach 0 cells/mm³. Usually other cell counts are within normal range. [1,2,3,4,5]
Peripheral blood smear This demonstrates a marked reduction or absence of neutrophils in the circulating blood. The presence of immature leukocyte precursors with co-existing anemia and/or thrombocytopenia suggest a hematologic malignancy such as leukemia and aplastic anemia. [1,2,3]
Blood culture and antibiotic sensitivity test Blood cultures have to be taken if an agranulocytosis patient present with fever. Several blood cultures for anaerobic and aerobic organisms are performed. Sites should include peripheral veins and catheters if present. [2,3,4,5]
Urinalysis, urine culture and antibiotic sensitivity test Complete fever workup should include urine full report, urine culture and antibiotic sensitivity test. This is done for early identification of any urinary tract infection and to treat with sensitive antibiotic before it progress into more severe conditions. [1.4,5,6,7]
Culture of infection foci Samples should be taken where may act as infection foci. Swabs have to be taken from wounds or catheter discharges. Sputum Gram stain and culture may useful in patients with respiratory tract infections. Stool cultures are done in suspicion of Clostridium difficile. [1,2,3,6,7]
Chest radiography Patients with fever, dyspnea and lung crepitation should undergo a chest x-ray in order to exclude/ diagnose pneumonia. [2,3,4,5]
Abdominal ultrasonography Abdominal ultrasonography is done to detect splenomegaly. [2,3,5]
Bone marrow biopsy Bone marrow aspirate should be obtained specially when bi/pancytopenia is detected. The usul site is posterior iliac crest. It helps to exclude lymphoma, metastatic carcinoma, myelofibrosis and granulomatous infection [1,2,3]
References
  1. MARCUS RE, GOLDMAN JM. Management of infection in the neutropenic patient. Br Med J (Clin Res Ed) [online] 1986 Aug 16, 293(6544):406-8 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/3091137
  2. SAMMUT SJ, MAZHAR D. Management of febrile neutropenia in an acute oncology service. QJM [online] 2012 Apr, 105(4):327-36 [viewed 12 July 2014] Available from: doi:10.1093/qjmed/hcr217
  3. JAMES RM, KINSEY SE. The investigation and management of chronic neutropenia in children. Arch Dis Child [online] 2006 Oct, 91(10):852-8 [viewed 12 July 2014] Available from: doi:10.1136/adc.2006.094706
  4. MANDELL LA. Management of the febrile neutropenic patient. Can Med Assoc J [online] 1983 Apr 15, 128(8):915-7 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/6831337
  5. WRIGHT JD, NEUGUT AI, ANANTH CV, LEWIN SN, WILDE ET, LU YS, HERZOG TJ, HERSHMAN DL. Deviations from guideline-based therapy for febrile neutropenia in cancer patients and their effect on outcomes. JAMA Intern Med [online] 2013 Apr 8, 173(7):559-68 [viewed 12 July 2014] Available from: doi:10.1001/jamainternmed.2013.2921
  6. KRELL D, JONES AL. Impact of effective prevention and management of febrile neutropenia Br J Cancer [online] 2009 Sep, 101(Suppl 1):S23-S26 [viewed 12 July 2014] Available from: doi:10.1038/sj.bjc.6605273
  7. KRZEMIENIECKI K, SEVELDA P, ERDKAMP F, SMAKAL M, SCHWENKGLENKS M, PUERTAS J, TROJAN A, SZABO Z, BENDALL K, MAENPAA J. Neutropenia management and granulocyte colony-stimulating factor use in patients with solid tumours receiving myelotoxic chemotherapy--findings from clinical practice. Support Care Cancer [online] 2014 Mar, 22(3):667-77 [viewed 12 July 2014] Available from: doi:10.1007/s00520-013-2021-2

Management - General Measures

Fact Explanation
Removal of any triggering drug In case of drug induced agranulocytosis, the drug which is known to cause the disease should be stopped administration. If the exact drug remains unknown, all drugs the patient is on should be temporarily stopped until the etiology is established. [1,2,3]
Patient education Good hygiene, including frequent hand washing and good dental care, such as regular tooth brushing and flossing should be practiced. Avoiding contact with sick people, always wearing shoes, cleaning cuts and scrapes, then covering them with a bandage, using an electric shaver rather than a razor, avoiding animal waste, avoiding unpasteurized dairy foods, under cooked meat and raw fruits, vegetables are important things to follow in order to prevent infections. [1,2,3,4]
Laxatives Impacted stools can act as a nidus for infections. Administration of stool softeners helps in preventing such infections. [1,2,3,4]
Skin care Proper and prompt care should be instituted in case of skin or wound abrasion. [1,2,5]
Nursing care Continuous nursing care and monitoring is needed as this patients may not show usual signs of an infection because of lack of the neutrophils to produce sufficient signs. Fever or chills may be the only indication of infection Other signs such as change in cough or new cough, sore throat or new mouth sore, burning or pain with urination, redness or swelling in any area, catheter site that is painful or sore, diarrhea, pain in abdomen or rectum and change in mental status are the other aspects should be considered continuously. Nursing makes an important impact on the outcome of care through interventions that help to prevent, monitor and educate. These interventions may save the life of patients with neutropenia. Patients should be placed into a single room if neutrophils are less than 500/µL and/or they demonstrate signs of infection. If patients are “well” with no obvious signs of infection and the neutrophils are 500/µL, they may be nursed in a multi-bed room if no single room is available, as long as no other patients in that room are infectious. A protective isolation sign should be displayed at the door (or above the patient bed in multi bed room). Staff caring for the patient should be infection free. Any staff must clean their hands with alcohol hand rub or use antimicrobial soap (containing chlorhexidine) and water prior to any activity with the patient. A mask is not necessary. Gloves/gowns/aprons and waste should be used in accordance with standard precautions. Strict adherence to standard care of peripheral cannula and wounds should occur. Visitors should be screened for illness. Visitors who have an infection or have been in close contact with an infection should be excluded from visiting until 48 hours symptom free. [1,2,5,6]
References
  1. SAMMUT SJ, MAZHAR D. Management of febrile neutropenia in an acute oncology service. QJM [online] 2012 Apr, 105(4):327-36 [viewed 12 July 2014] Available from: doi:10.1093/qjmed/hcr217
  2. MARCUS RE, GOLDMAN JM. Management of infection in the neutropenic patient. Br Med J (Clin Res Ed) [online] 1986 Aug 16, 293(6544):406-8 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/3091137
  3. KRELL D, JONES AL. Impact of effective prevention and management of febrile neutropenia Br J Cancer [online] 2009 Sep, 101(Suppl 1):S23-S26 [viewed 12 July 2014] Available from: doi:10.1038/sj.bjc.6605273
  4. CULLEN M, BAIJAL S. Prevention of febrile neutropenia: use of prophylactic antibiotics Br J Cancer [online] 2009 Sep, 101(Suppl 1):S11-S14 [viewed 12 July 2014] Available from: doi:10.1038/sj.bjc.6605270
  5. KRZEMIENIECKI K, SEVELDA P, ERDKAMP F, SMAKAL M, SCHWENKGLENKS M, PUERTAS J, TROJAN A, SZABO Z, BENDALL K, MAENPAA J. Neutropenia management and granulocyte colony-stimulating factor use in patients with solid tumours receiving myelotoxic chemotherapy--findings from clinical practice. Support Care Cancer [online] 2014 Mar, 22(3):667-77 [viewed 12 July 2014] Available from: doi:10.1007/s00520-013-2021-2
  6. MARRS JOYCE A.. Care of Patients With Neutropenia. Clinical Journal of Oncology Nursing [online] December, 10(2):164-166 [viewed 13 July 2014] Available from: doi:10.1188/06.CJON.164-166

Management - Specific Treatments

Fact Explanation
Antibiotics The most commonly used single antibiotic agent is a third generation cephalosporin (eg- ceftazidime, cefepime) or a ultra-broad-spectrum beta-lactam which belongs to the subgroup of carbapenem such as imipenem or meropenem. Gentamicin, ticarcillin-clavulanate potassium and piperacillin-tazobactam are some other substitutes. Vancomycin should be added if methicillin-resistant Staphylococcus aureus is suspected. [1,2,3,4,5]
Colony-stimulating factors (G-CSFs) G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. It is used for several types of neutropenia, including congenital types where it can be lifesaving. G-CSF also used for patients after chemotherapy as it shorten the duration of neutropenia. [1,2,3]
Granulocyte Transfusion Transfusion of granulocytes has several disadvantages as a treatment option. As they only lasts around 10 hours before destruction and its transfusion carries serious side effects, usage of it is debatable. However it may useful in several occasions. This could be considered in cases with gram-negative sepsis and no improvement in 24-48 hours. [2,3,4]
Splenectomy Usually surgery should be avoided in a patient with neutropenia. But splenectomy is the treatment of choice for those with agranulocytosis who get recurrent life-threatening bacterial infections. [1,2,3]
Other surgical procedures Though generally discouraged, surgeries have to be done in some instances where mere antibiotic therapy will not work until the pus collection is removed. (eg- abscess, cholecystitis, cholangitis) [1,2,3]
References
  1. MARCUS RE, GOLDMAN JM. Management of infection in the neutropenic patient. Br Med J (Clin Res Ed) [online] 1986 Aug 16, 293(6544):406-8 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/3091137
  2. SAMMUT SJ, MAZHAR D. Management of febrile neutropenia in an acute oncology service. QJM [online] 2012 Apr, 105(4):327-36 [viewed 12 July 2014] Available from: doi:10.1093/qjmed/hcr217
  3. MANDELL LA. Management of the febrile neutropenic patient. Can Med Assoc J [online] 1983 Apr 15, 128(8):915-7 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/6831337
  4. KRELL D, JONES AL. Impact of effective prevention and management of febrile neutropenia Br J Cancer [online] 2009 Sep, 101(Suppl 1):S23-S26 [viewed 12 July 2014] Available from: doi:10.1038/sj.bjc.6605273
  5. CULLEN M, BAIJAL S. Prevention of febrile neutropenia: use of prophylactic antibiotics Br J Cancer [online] 2009 Sep, 101(Suppl 1):S11-S14 [viewed 12 July 2014] Available from: doi:10.1038/sj.bjc.6605270