critical care leucopenia

1. Granulocytopenia
Critical care clinics
Dr Pratyush Chaudhuri

2. Granulocytopenia is defined as a
reduced number of blood granulocytes,
namely neutrophils, eosinophils, and
basophils.

3. Granulocytopenia (neutropenia) is defined
specifically as
A decrease in the number of circulating
neutrophils in the nonmarginal pool,
which constitutes 4-5% of total body
neutrophil stores.

4. Value of less than 1500/mm3 is used to
define neutropenia.

5. Neutropenia is classified as mild,
moderate, or severe, based on the ANC,
which is calculated by

Absolute Neutrophil count= [Total WBC X N% ] + band forms
 Mild neutropenia - 1000-1500/mm3
 moderate neutropenia - 500-1000/mm3
 severe neutropenia - less than 500/mm3.

6. Neutropenia can be caused by
 insufficient or injured bone marrow stem
cells
shifts in neutrophils from the circulating
pool to the marginal blood or tissue
pools
increased destruction in the circulation
combination of these mechanisms.

7.  Intravascular stimulation of neutrophils by plasma-
activated complement 5 (C5a) and endotoxin may
cause increased margination along the vascular
endothelium, decreasing the number of circulating
neutrophils.
 The term pseudoneutropenia refers to neutropenia
caused by increased margination.

8. Pathophysiology
Disorders of the pluripotent myeloid
stem cells and committed myeloid
progenitor cells include some congenital
forms of neutropenia
aplastic anemia
acute leukemia
myelodysplastic syndrome.

9. Other examples include
 bone marrow tumor infiltration
 Radiation
 infection (especially viral)
 bone marrow fibrosis.
 Cancer chemotherapy, other drugs, and toxins may
damage hematopoietic precursors by directly affecting
bone marrow.

10. immunologic destruction triggered by
autoimmune diseases (eg, Felty
syndrome) and by drugs acting as
haptens.
The risk of serious infection increases as
the ANC falls to the severely neutropenic
range (<500/mm3).

11. The duration of severe neutropenia
directly correlates with the total
incidence of all infections and those
infections that are life threatening.

12. Bacterial organisms most often cause fever and
infection in neutropenic patients.
 gram-negative aerobic bacteria (eg, Escherichia coli,
Klebsiella species, Pseudomonas aeruginosa)
 gram-positive cocci, especially Staphylococcus
species and Streptococcus viridans.

13. Note
 After treating neutropenic patients with broad-
spectrum antibiotics for several days, superinfection
with fungi is common.

14.  Indian Data awaited
 Data from US National Health and Nutritional
examination 1999 to 2004 survey showed the
prevalence of neutropenia was
 4.5% among black participants relative to 0.79% in
white individuals and 0.38% in Mexican-Americans
participants.

15. History
Hallmarks of significant neutropenia are
fever and recurrent infection, primarily of
the oropharynx and skin. Obtaining a
careful drug history is important.

16.  Common presenting symptoms of neutropenia
 Low-grade fever
 Sore mouth
 Odynophagia
 Gingival pain and swelling
 Skin abscesses
 Recurrent sinusitis and otitis
 Symptoms of pneumonia (eg, cough, dyspnea)
 Perirectal pain and irritation

17. Congenital neutropenia –
personal history of lifelong infections
family history of recurrent infections
limited survival.
Chronic, benign familial neutropenia –
long-standing neutropenia without an
increased risk of infection.

18. Physical findings on examination of a patient with
neutropenia may include the following:
 Fever
 Stomatitis
 Periodontal infection
 Cervical lymphadenopathy
 Skin infection
 Splenomegaly
 Associated petechial bleeding
 Perirectal infection
 Growth retardation in children

19. Acquired neutropenia (disorder of neutrophil
production)
Intrinsic bone marrow diseases
 Aplastic anemia
 Hematologic malignancy (eg, leukemia, lymphoma,
myelodysplasia, myeloma)
 Ionizing radiation
 Tumor infiltration
 Granulomatous infection
 Myelofibrosis

20. Drugs, including, but not limited to, the following:
 Acetaminophen
 Aminoglutethemide
 Antithyroid drugs: propylthiouracil,
carbimazole, methimazole
 Cytotoxic chemotherapeutic
agents
 Gold salts
 Chloramphenicol
 Indomethacin
 Phenylbutazone
 Phenothiazines
 Semi-synthetic penicillins
 Cephalosporins
 Antituberculosis drugs
 Trimethoprim/sulfamethoxazole
 Anticonvulsants
 Cimetidine
 Clonazepam
 Ranitidine
 Ibuprofen
 Hydralazine
 Captopril, enalapril
 Tocainide
 Chlorpropamide
 Benzodiazepines
 Ticlopidine
 Zidovudine
 Sulfasalazine
 Propranolol
 Digoxin
 Ticlopidine

21. Infection, including, but not limited to, the following:
 Bacterial sepsis
 Viral infections (eg, influenza, measles, Epstein Barr
virus [EBV], cytomegalovirus [CMV], viral hepatitis,
human immunodeficiency virus [HIV]-1)
 Toxoplasmosis
 Brucellosis
 Typhoid
 Tuberculosis
 Malaria
 Dengue fever
 Rickettsial infection
 Babesiosis

22. Acquired neutropenia (disorder of neutrophil
production)
Idiopathic
Nutritional deficiency
(eg, vitamin B-12, folate, copper, cachexia
and debilitated states)

23. Acquired neutropenia (disorder of neutrophil
production)
Acquired neutropenia (peripheral
destruction of neutrophils is usually
immune mediated)
Alloimmune neutropenia in the neonate
usually reflects a transplacental transfer
of maternal alloantibodies to neutrophil
antigens present on the neutrophils of
the fetus.

24. Drug immune-mediated neutropenia
 Aminopyrine
 Quinidine
 Cephalosporins
 Penicillins
 Sulfonamides
 Phenothiazines
 Phenylbutazone
 Hydralazine
 Other medications have been implicated.

25. Autoimmune neutropenia may be associated with the following:
 Crohn disease
 Rheumatoid arthritis (with or without Felty syndrome)
 Sjogren syndrome
 Chronic, autoimmune hepatitis
 Hodgkin lymphoma
 Systemic lupus erythematosus
 Thymoma
 Goodpasture disease
 Wegener granulomatosis
 Pure red blood cell (RBC) aplasia.
 Transfusion reactions.
 Large granular lymphocyte proliferation or leukemia

26. Acquired neutropenia (shifts of neutrophils from the
circulating to the marginated pool of neutrophils)
 Bacterial infection
 Cardiopulmonary bypass
 Hemodialysis
 Splenic sequestration
 Sepsis
 Congenital neutropenia
 Cyclic neutropenia
 Cartilage-hair hypoplasia syndrome
 Chediak-Higashi syndrome
 Dyskeratosis congenita
 Infantile genetic agranulocytosis (Kostmann syndrome)
 Lazy leukocyte syndrome
 Myelokathexis
 Shwachman-Diamond syndrome
 Reticular dysgenesis

27. Eosinopenia may be associated with the following:
 Acute bacterial infection
 Glucocorticoid administration
 Hypogammaglobulinemia
 Physical stress
 Thymoma
 Decreased circulating basophils may be associated with the following:
 Anaphylaxis
 Acute infection
 Drug-induced hypersensitivity
 Congenital absence of basophils
 Hemorrhage
 Hyperthyroidism
 Ionizing radiation
 Neoplasia
 Ovulation
 Urticaria
 Drugs (eg, corticosteroid, adrenocorticotropic hormone [ACTH] therapy, chemotherapeutic
agents, thyroid hormones)

28. Differential diagnosis
Acute Lymphoblastic
Leukemia
Influenza
Acute Myelogenous
Leukemia
Myelodysplastic Syndrome
Agranulocytosis
Myelophthisic Anemia
Aplastic Anemia
Neutropenia
Bone Marrow Failure
Paroxysmal Nocturnal
Hemoglobinuria
Brucellosis
Pernicious Anemia
 Cytomegalovirus
Sepsis, Bacterial
Ehrlichiosis
Splenomegaly
Felty Syndrome
Systemic Lupus
Erythematosus
Folic Acid Deficiency
Toxoplasmosis
Hairy Cell Leukemia
Tuberculosis
Hepatitis, Viral
Wegener Granulomatosis
Infectious Mononucleosis

29. Other Problems to Be Considered
Autoimmune diseases
Chronic myelomonocytic leukemia
Congenital neutropenia
Cyclic neutropenia
Drug-induced neutropenia
Large granular lymphocytic leukemia
Pseudoneutropenia

30. Work up
Laboratory Studies
Previous to a major workup, rule out
infectious and drug-induced causes of
neutropenia; then, obtain the following
laboratory studies:
Complete blood cell (CBC) count
Differential WBC count
Platelet count
Wright-stained peripheral smear

33. The following studies are applicable in some patients
with neutropenia:
 Antinuclear antibody (ANA)
 Rheumatoid factor (RF)
 Serum immunoglobulin (Ig) studies
 Liver function tests (LFTs)

34. Imaging Studies
 Perform long-bone radiographs if a form of
congenital neutropenia is suspected.
 Obtain liver-spleen radionuclide scans if the
presence of splenomegaly and splenic
sequestration are suspected in a patient with
neutropenia .

35. Other Tests
 Obtain vitamin B-12 and folate levels.
 infection workup, including blood cultures for
anaerobic and aerobic organisms.
 complete fever workup include the following:
 Urinalysis
 Urine culture and sensitivity
 Culture of wound or catheter discharge
 Stool for Clostridium difficile
 Skin biopsy, if new erythematous and tender skin lesions are
present
 Broad-spectrum antibiotics should be started within 1
hour of cultures.

36. Procedures
bone marrow aspiration and obtain a
biopsy

37. Medical Care
Discontinue drugs if they are suspected.
Corticosteroid therapy could be effective
in immune-mediated neutropenia.
Correct nutritional deficiency (cobalamin
or folic acid deficiency) if detected.

38. Treat the fever as an infection, as follows:
 Third-generation cephalosporins (eg, ceftazidime,
cefepime) or imipenem-cilastatin and meropenem can
be used as a single agent.
 Gentamicin or another aminoglycoside should be
added if the neutropenic patient's condition is unstable
or the individual appears septic.
 Beta-lactam antibiotics (eg, ticarcillin, piperacillin) are
usually used in combination with a third-generation
cephalosporin or an aminoglycoside.
 Vancomycin should be added if methicillin-resistant
Staphylococcus aureus or Corynebacterium species is
suspected.

39.  If the neutropenic patient's fever does not
respond within 4-5 days or if the fever recurs
with the administration of broad-spectrum
antibiotics after an initial afebrile interval
 consider adding empiric antifungal coverage
with amphotericin B (preferably lipid
formulation)
 a broad-spectrum azole (eg, voriconazole)
 an echinocandin (eg, caspofungin).

40. Fever in patients with low-risk
neutropenia can be treated on an
outpatient basis with oral antibiotics.

41. Myeloid growth factors
granulocyte colony-stimulating factors
(GCSFs)
granulocyte-macrophage colony-
stimulating factor (GM-CSFs)
may shorten the duration of neutropenia in
patients who have undergone
chemotherapy.

42. Neutrophil (granulocyte) transfusion
some clinical usefulness in treating
neonatal sepsis.

43. Cyclic neutropenia patients .
Congenital neutropenia patients.
Important supportive measures
Careful handwashing
Meticulous care of indwelling catheters

44. Surgical Care
 In individuals with neutropenia and Felty syndrome
who have recurrent life-threatening bacterial infections,
splenectomy is the treatment of choice.
 Indwelling central venous catheters should be
removed in febrile neutropenic patients if septic
thromboembolism is suspected. Other indications for
catheter removal include the following:
 Corynebacterium jeikeium infection
 Infection with Candida species
 Polymicrobial infection
 Persistent fevers
 Pocket-space abscess
 Tunnel infections

45. Thank You…