Agranulocytosis

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.

The incidence rate of the disorder is set at a value of circa 8 / 100.000.

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].

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].

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 If the patient is suffering from drug-induced agranulocytosis, then the drug which is cause of the problem will be withdrawn and a substitute drug would then be suggested.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].

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.

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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.

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