(Agranulocytosis; Granulocytopenia)
Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever is present during most serious infections. Diagnosis is by WBC count with differential, but evaluation requires identification of the cause. If fever is present, infection is presumed, and immediate, empiric broad-spectrum antibiotics are necessary, especially if the neutropenia is severe. Treatment with granulocyte colony-stimulating factor is sometimes helpful.
Neutrophils (granulocytes) are the body’s main defense against bacterial infections and fungal infections. When neutropenia is present, the inflammatory response to such infections is ineffective.
The normal lower limit of the neutrophil count (total WBC × % neutrophils and bands) is 1500/μL in whites and is somewhat lower in blacks (about 1200/μL). Neutrophil counts are not as stable as other cell counts and may vary considerably over short periods, depending on many factors such as activity status, anxiety, infections, and drugs. Thus, several measurements may be needed when determining the severity of neutropenia.
Severity of neutropenia relates to the relative risk of infection and is classified as follows:
Mild (1000 to 1500/μL)
Moderate (500 to 1000/μL)
Severe (< 500/μL)
When neutrophil counts fall to <500/μL, endogenous microbial flora (eg, in the mouth or gut) can cause infections. If the count falls to < 200/μL, the inflammatory response may be muted and the usual inflammatory findings of leukocytosis or WBCs in the urine or at the site of infection may not occur. Acute, severe neutropenia, particularly if another factor (eg, cancer) is present, significantly impairs the immune system and can lead to rapidly fatal infections. The integrity of the skin and mucous membranes, the vascular supply to tissue, and the nutritional status of the patient also influence the risk of infections.
The most frequently occurring infections in patients with profound neutropenia are
Cellulitis
Furunculosis
Pneumonia
Septicemia
Vascular catheters and other puncture sites confer extra risk of skin infections; the most common bacterial causes are coagulase-negative staphylococci and Staphylococcus aureus, but other gram-positive and gram-negative infections also occur. Stomatitis, gingivitis, perirectal inflammation, colitis, sinusitis, paronychia, and otitis media often occur. Patients with prolonged neutropenia after hematopoietic stem cell transplantation or chemotherapy and patients receiving high doses of corticosteroids are predisposed to fungal infections.
Neutropenia due to intrinsic defects in myeloid cells or their precursors
Impaired production
Chronic neutropenia (lasting months to years) usually arises as a result of
Reduced production
Excessive splenic sequestration
Neutropenia also may be classified as primary due to an intrinsic defect in marrow myeloid cells or as secondary (due to factors extrinsic to marrow myeloid cells—see table Classification of Neutropenias).
Classification of Neutropenias
Aplastic anemia
Chronic idiopathic neutropenia, including benign neutropenia
Cyclic neutropenia
Myelodysplasia
Neutropenia associated with dysgammaglobulinemia
Paroxysmal nocturnal hemoglobinuria
Severe congenital neutropenia (Kostmann syndrome)
Syndrome-associated neutropenias (eg, cartilage-hair hypoplasia syndrome, dyskeratosis congenita, glycogen storage disease type IB, WHIM* syndrome, Shwachman-Diamond syndrome)
Secondary neutropenias
Alcoholism
Autoimmune neutropenia, including chronic secondary neutropenia in AIDS
Bone marrow replacement (eg, due to cancer, myelofibrosis, granuloma, or Gaucher cells)
Cytotoxic chemotherapy or radiation therapy
Drug-induced neutropenia
Folate deficiency, vitamin B12 deficiency, or severe undernutrition
Hypersplenism
Infection
T cell large granular lymphocyte disease
*WHIM = warts, hypogammaglobulinemia, infections, myelokathexis.
Neutropenia caused by intrinsic defects in myeloid cells or their precursors
Neutropenia caused by intrinsic defects in myeloid cells or their precursors is uncommon, but when present, the most common causes include
Chronic idiopathic neutropenia
Congenital neutropenia
Chronic benign neutropenia is a type of chronic idiopathic neutropenia in which the rest of the immune system appears to remain intact; even with neutrophil counts < 200/μL, serious infections usually do not occur, probably because neutrophils are sometimes produced in adequate quantities in response to infection. It is most common in women.
Severe congenital neutropenia (SCN, or Kostmann syndrome) is a heterogenous group of rare disorders that are characterized by an arrest in myeloid maturation at the promyelocyte stage in the bone marrow, resulting in an absolute neutrophil count of < 200/μL and significant infections starting in infancy. SCN can be autosomal dominant or recessive, X-linked, or sporadic. Several genetic abnormalities that cause SCN have been identified, including mutations affecting neutrophil elastase (ELANE/ELA2), HAX1, GFI1, and the G-CSF receptor (CSF3R). Most SCN patients will respond to chronic growth factor therapy, but hematopoietic stem cell transplantation may need to be considered for poor responders. SCN patients have an increased risk of developing myelodysplasia or acute myelogenous leukemia.
Cyclic neutropenia is a rare congenital granulocytopoietic disorder, usually transmitted in an autosomal dominant fashion and usually caused by a mutation in the gene for neutrophil elastase (ELANE/ELA2), resulting in abnormal apoptosis. It is characterized by regular, periodic oscillations in the number of peripheral neutrophils. The mean oscillatory period is 21 ± 3 days. Cycling of other blood cells is also evident in most cases.
Benign ethnic neutropenia (BEN) occurs in members of some ethnic groups (eg, some people of African, Middle Eastern, and Jewish descent). They normally have lower neutrophil counts but do not have increased risk of infection. In some cases this finding has been linked to the Duffy RBC antigen; some experts think neutropenia in these populations is related to protection from malaria.
Neutropenia can also result from bone marrow failure due to rare congenital syndromes (eg, cartilage-hair hypoplasia syndrome, Chédiak-Higashi syndrome, dyskeratosis congenita, glycogen storage disease type IB, Shwachman-Diamond syndrome, warts, hypogammaglobulinemia, infections, myelokathexis [WHIM] syndrome). Neutropenia is also a feature of myelodysplasia, where it may be accompanied by megaloblastoid features in the bone marrow, and of aplastic anemia and can occur in dysgammaglobulinemia and paroxysmal nocturnal hemoglobinemia.
Secondary neutropenia
Secondary neutropenia can result from use of certain drugs, bone marrow infiltration or replacement, certain infections, or immune reactions.
The most common causes include
Drugs
Infections and immune reactions
Marrow infiltrative processes
Drug-induced neutropenia is one of the most common causes of neutropenia. Drugs can decrease neutrophil production through toxic, idiosyncratic, or hypersensitivity mechanisms; or they can increase peripheral neutrophil destruction through immune mechanisms. Only the toxic mechanism (eg, with phenothiazines) causes dose-related neutropenia.
Severe dose-related neutropenia occurs predictably after cytotoxic cancer drugs or radiation therapy due to suppression of bone marrow production.
Idiosyncratic reactions are unpredictable and occur with a wide variety of drugs, including alternative medicine preparations or extracts, and toxins.
Hypersensitivity reactions are rare and occasionally involve anticonvulsants (eg, phenytoin, phenobarbital). These reactions may last for only a few days or for months or years. Often, hepatitis, nephritis, pneumonitis, or aplastic anemia accompanies hypersensitivity-induced neutropenia.
Immune-mediated drug-induced neutropenia, thought to arise from drugs that act as haptens to stimulate antibody formation, usually persists for about 1 wk after the drug is stopped. It may result from aminopyrine, propylthiouracil, penicillin, or other antibiotics.
Neutropenia due to ineffective bone marrow production can occur in megaloblastic anemias caused by vitamin B12 deficiency or folate deficiency. Usually, macrocytic anemia and sometimes mild thrombocytopenia develop simultaneously. Ineffective production can also accompany myelodysplastic disorders.
Bone marrow infiltration by leukemia, myeloma, lymphoma, or metastatic solid tumors (eg, breast cancer, prostate cancer) can impair neutrophil production. Tumor-induced myelofibrosis may further exacerbate neutropenia. Myelofibrosis can also occur due to granulomatous infections, Gaucher disease, and radiation therapy.
Hypersplenism of any cause can lead to moderate neutropenia, thrombocytopenia, and anemia.
Infections can cause neutropenia by impairing neutrophil production or by inducing immune destruction or rapid use of neutrophils. Sepsis is a particularly serious cause. Neutropenia that occurs with common childhood viral diseases develops during the first 1 to 2 days of illness and may persist for 3 to 8 days. Transient neutropenia may also result from virus- or endotoxemia-induced redistribution of neutrophils from the circulating to the marginal pool. Alcohol may contribute to neutropenia by inhibiting the neutrophilic response of the marrow during some infections (eg, pneumococcal pneumonia).
Immune defects can cause neutropenia. Neonatal isoimmune neutropenia can occur with fetal/maternal neutrophil antigen incompatibility associated with transplacental transfer of IgG antibodies against the newborn’s neutrophils (most commonly to HNA-1 antigens). Autoimmune neutropenia can occur at any age and may be operative in many cases of idiopathic chronic neutropenia. Testing for antineutrophil antibodies (immunofluorescence, agglutination, or flow cytometry) is not always available or reliable.
Chronic secondary neutropenia often accompanies HIV infection because of impaired production of neutrophils and accelerated destruction of neutrophils by antibodies. Autoimmune neutropenias may be acute, chronic, or episodic. They may involve antibodies directed against circulating neutrophils or neutrophil precursor cells. They may also involve cytokines (eg, gamma interferon, tumor necrosis factor) that can cause neutrophil apoptosis. Most patients with autoimmune neutropenia have an underlying autoimmune disorder or lymphoproliferative disorder (eg, SLE, Felty syndrome).
Neutropenia is asymptomatic until infection develops. Fever is often the only indication of infection. Typical signs of focal inflammation (erythema, swelling, pain, infiltrates) may be muted or absent. Focal symptoms (eg, oral ulcers) may develop but are often subtle. Patients with drug-induced neutropenia due to hypersensitivity may have a fever, rash, and lymphadenopathy as a result of the hypersensitivity.
Some patients with chronic benign neutropenia and neutrophil counts < 200/μL do not experience many serious infections. Patients with cyclic neutropenia or severe congenital neutropenia tend to have episodes of oral ulcers, stomatitis, or pharyngitis and lymph node enlargement during severe neutropenia. Pneumonias and septicemia often occur.
Clinical suspicion (repeated or unusual infections)
Confirmatory CBC with differential
Evaluation for infection with cultures and imaging
Identification of mechanism and cause of neutropenia
Neutropenia is suspected in patients with frequent, severe, or unusual infections or in patients at risk (eg, those receiving cytotoxic drugs or radiation therapy). Confirmation is by CBC with differential.
Evaluation for infection
The first priority is to determine whether an infection is present. Because infection may be subtle, physical examination systematically assesses the most common primary sites of infection: mucosal surfaces, such as the alimentary tract (gums, pharynx, anus); lungs; abdomen; urinary tract; skin and fingernails; venipuncture sites; and vascular catheters.
If neutropenia is acute or severe, laboratory evaluation must proceed rapidly.
Cultures are the mainstay of evaluation. At least 2 sets of bacterial and fungal blood cultures are obtained from all febrile patients; if an indwelling IV catheter is present, cultures are drawn from the catheter and from a separate peripheral vein. Persistent or chronic drainage material is also cultured for fungi and atypical mycobacteria. Mucosal ulcers are swabbed and cultured for herpes virus. Skin lesions are aspirated or biopsied for cytology and culture. Samples for urinalysis and urine cultures are obtained from all patients. If diarrhea is present, stool is evaluated for enteric bacterial pathogens and Clostridium difficile toxins. Sputum cultures are obtained to evaluate for pulmonary infections.
Imaging studies are helpful. Chest x-rays are done on all patients. A chest CT may also be necessary in immunosuppressed patients. CT of the paranasal sinuses may be helpful if symptoms or signs of sinusitis (eg, positional headache, upper tooth or maxillary pain, facial swelling, nasal discharge) are present. CT scan of the abdomen is usually done if symptoms (eg, pain) or history (eg, recent surgery) suggests an intra-abdominal infection.
Identification of cause
Next, mechanism and cause of neutropenia are determined. The history addresses all drugs, other preparations, and possible toxin exposure or ingestion.
Physical examination addresses the presence of splenomegaly and signs of other underlying disorders (eg, arthritis, lymphadenopathy).
If no obvious cause is identified (eg, chemotherapy), the most important test is Bone marrow examination
Bone marrow examination determines whether neutropenia is due to decreased marrow production or is secondary to increased cell destruction (determined by normal or increased production of the myeloid cells). Bone marrow examination may also indicate the specific cause of the neutropenia (eg, aplastic anemia, myelofibrosis, leukemia). Additional marrow studies (eg, cytogenetic analysis; special stains and flow cytometry for detecting leukemia, other malignant disorders, and infections) are done.
Further testing for the cause of neutropenia may be necessary, depending on the diagnoses suspected. In patients at risk of nutritional deficiencies, levels of copper, folate, and vitamin B12 are determined. Testing for the presence of antineutrophil antibodies is done if immune neutropenia is suspected. Differentiation between neutropenia caused by certain antibiotics and infection can sometimes be difficult. The WBC count just before the start of antibiotic treatment usually reflects the change in blood count due to the infection.
Patients who have had chronic neutropenia since infancy and a history of recurrent fevers and chronic gingivitis have WBC counts with differential done 3 times/wk for 6 wk, so that periodicity suggestive of cyclic neutropenia can be evaluated. Platelet and reticulocyte counts are done simultaneously. In patients with cyclic neutropenia, eosinophils, reticulocytes, and platelets frequently cycle synchronously with the neutrophils, whereas monocytes and lymphocytes may cycle out of phase.
Treatment of associated conditions (eg, infections, stomatitis)
Sometimes antibiotic prophylaxis
Myeloid growth factors
Discontinuation of suspected etiologic agent (eg, drug)
Sometimes corticosteroids
Acute neutropenia
Suspected infections are always treated immediately. If fever or hypotension is present, serious infection is assumed, and empiric, high-dose, broad-spectrum antibiotics are given IV. Regimen selection is based on the most likely infecting organisms, the antimicrobial susceptibility of pathogens at that particular institution, and the regimen’s potential toxicity. Because of the risk of creating resistant organisms, vancomycin is used only if gram-positive organisms resistant to other drugs are suspected.
Indwelling vascular catheters can usually remain in place even if bacteremia is suspected or documented, but removal is considered if infections involve S. aureus or Bacillus sp, Corynebacterium sp, or Candida sp or if blood cultures are persistently positive despite appropriate antibiotics. Infections caused by coagulase-negative staphylococci generally resolve with antimicrobial therapy alone. Indwelling Foley catheters can also predispose to infections in neutropenic patients, and change or removal of the catheter should be considered for persistent urinary infections.
If cultures are positive, antibiotic therapy is adjusted to the results of sensitivity tests. If a patient defervesces within 72 h, antibiotics are continued for at least 7 days and until the patient has no symptoms or signs of infection. When neutropenia is transient (such as that following myelosuppressive chemotherapy), antibiotic therapy is usually continued until the neutrophil count is > 500/μL; however, stopping antimicrobials can be considered in selected patients with persistent neutropenia, especially those in whom symptoms and signs of inflammation have resolved, if cultures remain negative.
Fever that persists > 72 h despite antibiotic therapy suggests a nonbacterial cause, infection with a resistant species, a superinfection with a 2nd bacterial species, inadequate serum or tissue levels of the antibiotics, or localized infection, such as an abscess. Neutropenic patients with persistent fever are reassessed every 2 to 4 days with physical examination, cultures, and chest x-ray. If the patient is well except for the presence of fever, the initial antibiotic regimen can be continued, and drug-induced fever should be considered. If the patient is deteriorating, alteration of the antimicrobial regimen is considered.
Fungal infections are the most likely cause of persistent fevers and deterioration. Antifungal therapy is added empirically if unexplained fever persists after 3 to 4 days of broad-spectrum antibiotic therapy. Selection of the specific antifungal drug (eg, fluconazole, caspofungin, voriconazole, posaconazole) depends on the type of risk (eg, duration and severity of neutropenia, past history of fungal infection, persistent fever despite use of narrower spectrum antifungal drug) and should be guided by an infectious disease specialist. If fever persists after 3 wk of empiric therapy (including 2 wk of antifungal therapy) and the neutropenia has resolved, then stopping all antimicrobials can be considered and the cause of fever reevaluated.
For afebrile patients with neutropenia, antibiotic prophylaxis with fluoroquinolones (levofloxacin, ciprofloxacin) is used in some centers for patients who receive chemotherapy regimens that commonly result in neutrophils ≤ 100/µL for > 7 days. Prophylaxis is usually started by the treating oncologist. Antibiotics are continued until the neutrophil count increases to > 1500/µL. Also, antifungal therapy can be given for afebrile neutropenic patients at higher risk of fungal infection (eg, after hematopoietic stem cell transplantation, intensive chemotherapy for acute myelogenous leukemia or a myelodysplastic disorder, prior fungal infections). Selection of the specific antifungal drug should be guided by an infectious disease specialist. Antibiotic and antifungal prophylaxis is not routinely recommended for afebrile neutropenic patients without risk factors who are anticipated to remain neutropenic for < 7 days on the basis of their specific chemotherapy regimen.
Myeloid growth factors (ie, granulocyte colony-stimulating factor [G-CSF]) are widely used to increase the neutrophil count and to prevent infections in patients with severe neutropenia (eg, after hematopoietic stem cell transplantation and intensive cancer chemotherapy). They are expensive. However, if the risk of febrile neutropenia is ≥ 30% (as assessed by neutrophil count < 500 μL, presence of infection during a previous cycle of chemotherapy, associated comorbid disease, or age > 75), growth factors are indicated. In general, most clinical benefit occurs when the growth factor is administered beginning about 24 h after completion of chemotherapy. Patients with neutropenia caused by an idiosyncratic drug reaction may also benefit from myeloid growth factors, particularly if a delayed recovery is anticipated. The dose for G-CSF (filgrastim) is 5 to 10 mcg/kg sc once/day, and the dose for pegylated G-CSF (pegfilgrastim) is 6 mg sc once per chemotherapy cycle.
Glucocorticoids, anabolic steroids, and vitamins do not stimulate neutrophil production but can affect distribution and destruction. If acute neutropenia is suspected to be drug- or toxin-induced, all potentially etiologic agents are stopped. If neutropenia develops during treatment with a drug known to induce low counts (eg, chloramphenicol), then switching to an alternative antibiotic may be helpful.
Saline or hydrogen peroxide gargles every few hours, liquid oral rinses (containing viscous lidocaine, diphenhydramine, and liquid antacid), anesthetic lozenges (benzocaine 15 mg q 3 or 4 h), or chlorhexidine mouth rinses (1% solution) bid or tid may relieve the discomfort of stomatitis with oropharyngeal ulcerations. Oral or esophageal candidiasis is treated with nystatin (400,000 to 600,000 units oral rinse qid; swallowed if esophagitis is present), clotrimazole troche (10 mg slowly dissolved in the mouth 5 times a day), or systemic antifungal drugs (eg, fluconazole). A semisolid or liquid diet may be necessary during acute stomatitis or esophagitis, and topical analgesics (eg,viscous lidocaine) may be needed to minimize discomfort.
Chronic neutropenia
Neutrophil production in congenital neutropenia, cyclic neutropenia, and idiopathic neutropenia can be increased with administration of G-CSF 1 to 10 mcg/kg sc once/day. Effectiveness can be maintained with daily or intermittent G-CSF for months or years. Long-term G-CSF has also been used in other patients with chronic neutropenia, including those with myelodysplasia, HIV, and autoimmune disorders. In general, neutrophil counts increase, although clinical benefits are less clear, especially for patients who do not have severe neutropenia. For patients with autoimmune disorders or who have had an organ transplant, cyclosporine can also be beneficial.
In some patients with accelerated neutrophil destruction caused by autoimmune disorders, corticosteroids (generally, prednisone 0.5 to 1.0 mg/kg po once/day) can increase blood neutrophils. This increase often can be maintained with alternate-day G-CSF therapy.
Splenectomy has been used in the past to increase the neutrophil count in some patients with splenomegaly and splenic sequestration of neutrophils (eg, Felty syndrome); however, because growth factors and other newer therapies are often effective, splenectomy should be avoided in most patients. Splenectomy can be considered for patients with persistent painful splenomegaly or with severe neutropenia (ie, < 500/μL) and serious problems with infections in whom other treatments have failed. Patients should be vaccinated against infections caused by Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae before splenectomy because splenectomy predisposes patients to infection by encapsulated organisms.
Neutropenia predisposes to bacterial and fungal infections.
The risk of infection is proportional to the severity of neutropenia; patients with neutrophil counts < 500/μL are at greatest risk.
Because the inflammatory response is limited, clinical findings may be muted, although fever is usually present.
Febrile neutropenic patients are treated empirically with broad-spectrum antibiotics pending definitive identification of infection.
Antibiotic prophylaxis is indicated in high-risk patients.
Drugs causing agranulocytosis or low white cell count
Many drugs can cause agranulocytosis and neutropenia. The mechanism of neutropenia can be varied depending on the drug. Many anti- neoplastic drugs cause agranulocytosis and neutropenia by bone marrow suppression. Neutropenia and agranulocytosis can also result from antibody or compliment mediated damage to the stem cells. Some drugs may cause increased peripheral destruction of white cells. About three fourth of all agranulocytosis in the United States is related to drugs. Procainamide, anti-thyroid drugs and sulfasalazine are at the top of the list of drugs causing this problem. Most agranulocytosis is related to the direct effect related to its dose. Phenothiazines, semi-synthetic penicillins, non-steroidal anti-inflammatory drugs (NSAIDs), aminopyrine derivatives, benzodiazepines, barbiturate, gold compounds, sulfonamides, and anti-thyroid medications are the most common causes of neutropenia and agranulocytosis. The neutropenia manifests in about one two weeks after exposure to these drugs. Degree of neutropenia depends upon the dose and duration of exposure. Recovery usually occurs within few days of stopping the drug. The marrow recovery may take 10 to 14 days. Some time a rebound leukocytosis may occur. If the neutropenia is not very severe and the medication is an essential drug for the patient, some times the drug may be continued with under close monitoring. As long as absolute neutrophil count is above 500 to 700 and there is no active infection the drug may be continued if needed. If a bone marrow biopsy is done and it shows cellular bone marrow this might suggest peripheral destruction of white cells and this may be clinically less relevant.
List of drugs that causes agranulocytosis or neutropenia sorted as per probability
(Anti-neoplastic drugs are not included)
Dipyrone
Mianserin
Sulfasalazine
Co-trimoxazole
Anti-arrythmic agents
Procainamide
Ajmaline
Tocainide
Aprindine
Amiodarone
Penicillins
Amoxycillin
Aziocillin
Benzylpenicillin
Phenethicillin
Cloaxacillin and penicillin
Thiouracil derivatives
Methyl thiouracil
Propyl thiourcil
Phenylbutazone
Cimetidine
Penicillamine
Diclofenac
Carbamazepine
ACE-Inhibitors
Captopril
Enalapril
Hydrochlorothiazide with potassium sparing diuretics
Indomethacine
Cephalosporins
Cephalexin
Cepahazolin
Cefuroxime
Cefitaxime
Cephradine
Oxyphenbutazone
Nitrofurantoin
Salicylic acid derivatives
Clozapine
Carbimazone
Sulphonylurea derivatives
Glibenclamide
Tolbutamide
Methyldopa
Thiamazole
Nucleosides
Aminoglutethimide
Ibuprofen
Pentazocine
Levamizole
Promethazine
Chloramphinicol
Acetaminophen and combinations
Perazine
Mebhydrolin
Ranitidine
Imipramine
Miscellaneous drugs (relatively lower probability)
Phenytoin
Chlorthalidone
Sulphamethizole
Norfloxacin
Naproxen
Clomipramine
Trazodone
Omeprazole
Alimemazine
Pirenzepine
Ticlopidine
Ibopamine
Hydralazine
Nifedipine
Nalidixic acid
Doxycycline
Clindamycin
Gentamycin
Fusidic acid
Dapsone
Azapropazone
Propyphenazone
Sulindac
Piroxicam
Pirprofen
Niflumic acid
Allopurinol
Glafenine
Valproate
Levadopa with carbidopa
Chlorpramazine
Haloperidol
spironolactone
Zuclopenthixol
Zopiclone
Cinnarizine
Metronidazole
Pyrimethamine combinations
Thophylline
Did you know?
Many drugs can cause agranulocytosis and neutropenia. The mechanism of neutropenia can be varied depending on the drug. Many anti- neoplastic drugs cause agranulocytosis and neutropenia by bone marrow suppression. Neutropenia and agranulocytosis can also result from antibody or compliment mediated damage to the stem cells. Some drugs may cause increased peripheral destruction of white cells. About three fourth of all agranulocytosis in the United States is related to drugs.
Drugs causing agranulocytosis or low white cell count
Many drugs can cause agranulocytosis and neutropenia. The mechanism of neutropenia can be varied depending on the drug. Many anti- neoplastic drugs cause agranulocytosis and neutropenia by bone marrow suppression. Neutropenia and agranulocytosis can also result from antibody or compliment mediated damage to the stem cells. Some drugs may cause increased peripheral destruction of white cells. About three fourth of all agranulocytosis in the United States is related to drugs. Procainamide, anti-thyroid drugs and sulfasalazine are at the top of the list of drugs causing this problem. Most agranulocytosis is related to the direct effect related to its dose. Phenothiazines, semi-synthetic penicillins, non-steroidal anti-inflammatory drugs (NSAIDs), aminopyrine derivatives, benzodiazepines, barbiturate, gold compounds, sulfonamides, and anti-thyroid medications are the most common causes of neutropenia and agranulocytosis. The neutropenia manifests in about one two weeks after exposure to these drugs. Degree of neutropenia depends upon the dose and duration of exposure. Recovery usually occurs within few days of stopping the drug. The marrow recovery may take 10 to 14 days. Some time a rebound leukocytosis may occur. If the neutropenia is not very severe and the medication is an essential drug for the patient, some times the drug may be continued with under close monitoring. As long as absolute neutrophil count is above 500 to 700 and there is no active infection the drug may be continued if needed. If a bone marrow biopsy is done and it shows cellular bone marrow this might suggest peripheral destruction of white cells and this may be clinically less relevant.
List of drugs that causes agranulocytosis or neutropenia sorted as per probability
(Anti-neoplastic drugs are not included)
Dipyrone
Mianserin
Sulfasalazine
Co-trimoxazole
Anti-arrythmic agents
Procainamide
Ajmaline
Tocainide
Aprindine
Amiodarone
Penicillins
Amoxycillin
Aziocillin
Benzylpenicillin
Phenethicillin
Cloaxacillin and penicillin
Thiouracil derivatives
Methyl thiouracil
Propyl thiourcil
Phenylbutazone
Cimetidine
Penicillamine
Diclofenac
Carbamazepine
ACE-Inhibitors
Captopril
Enalapril
Hydrochlorothiazide with potassium sparing diuretics
Indomethacine
Cephalosporins
Cephalexin
Cepahazolin
Cefuroxime
Cefitaxime
Cephradine
Oxyphenbutazone
Nitrofurantoin
Salicylic acid derivatives
Clozapine
Carbimazone
Sulphonylurea derivatives
Glibenclamide
Tolbutamide
Methyldopa
Thiamazole
Nucleosides
Aminoglutethimide
Ibuprofen
Pentazocine
Levamizole
Promethazine
Chloramphinicol
Acetaminophen and combinations
Perazine
Mebhydrolin
Ranitidine
Imipramine
Miscellaneous drugs (relatively lower probability)
Phenytoin
Chlorthalidone
Sulphamethizole
Norfloxacin
Naproxen
Clomipramine
Trazodone
Omeprazole
Alimemazine
Pirenzepine
Ticlopidine
Ibopamine
Hydralazine
Nifedipine
Nalidixic acid
Doxycycline
Clindamycin
Gentamycin
Fusidic acid
Dapsone
Azapropazone
Propyphenazone
Sulindac
Piroxicam
Pirprofen
Niflumic acid
Allopurinol
Glafenine
Valproate
Levadopa with carbidopa
Chlorpramazine
Haloperidol
spironolactone
Zuclopenthixol
Zopiclone
Cinnarizine
Metronidazole
Pyrimethamine combinations
Thophylline
Did you know?
Many drugs can cause agranulocytosis and neutropenia. The mechanism of neutropenia can be varied depending on the drug. Many anti- neoplastic drugs cause agranulocytosis and neutropenia by bone marrow suppression. Neutropenia and agranulocytosis can also result from antibody or compliment mediated damage to the stem cells. Some drugs may cause increased peripheral destruction of white cells. About three fourth of all agranulocytosis in the United States is related to drugs.
Lymphocytopenia is a total lymphocyte count of < 1000/μL in adults or < 3000/μL in children < 2 yr. Sequelae include opportunistic infections and an increased risk of malignant and autoimmune disorders. If the CBC reveals lymphocytopenia, testing for immunodeficiency and analysis of lymphocyte subpopulations should follow. Treatment is directed at the underlying disorder.
Lymphocytes are components of the cellular immune system and include B cells and T cells, both of which are present in the peripheral blood; about 75% of the lymphocytes are T cells and 25% B cells.
The normal lymphocyte count in adults is 1000 to 4800/μL; in children < 2 yr, 3000 to 9500/μL. At age 6 yr, the lower limit of normal is 1500/μL. Different laboratories may have slightly different normal values.
Almost 65% of blood T cells are CD4+ (helper) T cells. Thus, most patients with lymphocytopenia have a reduced absolute number of T cells, particularly in the number of CD4+ T cells. The average number of CD4+ T cells in adult blood is 1100/μL (range, 300 to 1300/μL), and the average number of cells of the other major T-cell subgroup, CD8+ (suppressor) T cells, is 600/μL (range, 100 to 900/μL).
• Many disorders can decrease the number of lymphocytes in the blood, but viral infections (including AIDS) and undernutrition are the most common.
• People may have no symptoms, or they may have fever and other symptoms of an infection.
• A blood sample is used to make the diagnosis of lymphocytopenia, but a sample of bone marrow or lymph node may be needed to determine the cause.
• Doctors treat the cause of lymphocytopenia.
• Some people are given gamma globulin, and some benefit from stem cell transplantation.
Lymphocytopenia can be Acquired or Inherited
Acquired
AIDS
Other infectious disorders, including hepatitis, influenza, TB, typhoid fever, and sepsis
Dietary deficiency in patients with ethanol abuse, protein-energy undernutrition, or zinc deficiency
Protein losing enteropathy
Iatrogenic after use of cytotoxic chemotherapy, glucocorticoids, high-dose psoralen and ultraviolet A radiation therapy, lymphocyte antibody therapy, immunosuppressants, radiation therapy, or thoracic duct drainage
Systemic disorders with autoimmune features (eg, aplastic anemia, Hodgkin lymphoma, myasthenia gravis, protein-losing enteropathy, RA, chronic kidney disease, sarcoidosis, SLE, thermal injury)
Hereditary
Aplasia of lymphopoietic stem cells
Ataxia-telangiectasia
Cartilage-hair hypoplasia syndrome
Idiopathic CD4+ T lymphocytopenia
Immunodeficiency with thymoma
Severe combined immunodeficiency associated with a defect in the IL-2 receptor gamma-chain, deficiency of ADA (adenosine deaminase) or PNP(purine nucleoside phosphorylase) , or an unknown defect
Wiskott-Aldrich syndrome
Acquired lymphocytopenia
The most common causes include
• Protein-energy undernutrition
• AIDS and certain other viral infections
Protein-energy undernutrition is the most common cause worldwide.
AIDS is the most common infectious disease causing lymphocytopenia, which arises from destruction of CD4+ T cells infected with HIV. Lymphocytopenia may also reflect impaired lymphocyte production arising from destruction of thymic or lymphoid architecture. In acute viremia due to HIV or other viruses, lymphocytes may undergo accelerated destruction from active infections with the virus, may be trapped in the spleen or lymph nodes, or may migrate to the respiratory tract.
Iatrogenic lymphocytopenia is caused by cytotoxic chemotherapy, radiation therapy, or the administration of antilymphocyte globulin (or other lymphocyte antibodies). Long-term treatment for psoriasis using psoralen and ultraviolet A irradiation may destroy T cells. Glucocorticoids can induce lymphocyte destruction.
Lymphocytopenia may occur with lymphomas, autoimmune diseases such as SLE, rheumatoid arthritis, or myasthenia gravis, and protein-losing enteropathy.
Inherited lymphocytopenia
Inherited lymphocytopenia
Most commonly occurs in
• Severe combined immunodeficiency disorder
• Wiskott-Aldrich syndrome
It may occur with inherited immunodeficiency disorders and disorders that involve impaired lymphocyte production. Other inherited disorders, such as Wiskott-Aldrich syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency, may involve accelerated T-cell destruction. In many disorders, antibody production is also deficient.
Lymphocytopenia per se generally causes no symptoms. However, findings of an associated disorder may include
• Absent or diminished tonsils or lymph nodes, indicative of cellular immunodeficiency
• Skin abnormalities (eg, alopecia, eczema, pyoderma, telangiectasia)
• Evidence of hematologic disease (eg, pallor, petechiae, jaundice, mouth ulcers)
• Generalized lymphadenopathy and splenomegaly, which may suggest HIV infection or Hodgkin lymphoma
Patients with lymphocytopenia experience recurrent infections or develop infections with unusual organisms. Pneumocystis jirovecii, cytomegalovirus, rubeola, and varicella pneumonias often are fatal. Lymphocytopenia is also a risk factor for the development of cancers and for autoimmune disorders.
• Enlarged lymph nodes and an enlarged spleen, suggesting cancer or HIV infection
• Cough, runny nose, and fever, suggesting a respiratory viral infection
• Small tonsils or lymph nodes, suggesting an inherited immune system disorder
• Painful swollen joints and a rash, suggesting rheumatoid arthritis or systemic lupus erythematosus
• Clinical suspicion (repeated or unusual infections)
• CBC with differential
• Measurement of lymphocyte subpopulations and immunoglobulin levels
Lymphocytopenia is suspected in patients with recurrent viral, fungal, or parasitic infections but is usually detected incidentally on a CBC. P. jirovecii, cytomegalovirus, rubeola, or varicella pneumonias with lymphocytopenia suggest immunodeficiency. Lymphocyte subpopulations are measured in patients with lymphocytopenia. Measurement of immunoglobulin levels should also be done to evaluate antibody production. Patients with a history of recurrent infections undergo complete laboratory evaluation for immunodeficiency, even if initial screening tests are normal.
• Treatment of associated infections
• Treatment of underlying disorder
• Sometimes IV or subcutaneous immune globulin
• Possibly hematopoietic stem cell transplantation
In acquired lymphocytopenias, lymphocytopenia usually remits with removal of the underlying factor or successful treatment of the underlying disorder. IV or subcutaneous immune globulin is indicated if patients have chronic IgG deficiency, lymphocytopenia, and recurrent infections. Hematopoietic stem cell transplantation can be considered for all patients with congenital immunodeficiencies and may be curative.
• Lymphocytopenia is most often due to AIDS or undernutrition, but it also may be inherited or caused by various infections, drugs, or autoimmune disorders.
• Patients have recurrent viral, fungal, or parasitic infections.
• Lymphocyte subpopulations and immunoglobulin levels should be measured.
• Treatment is usually directed at the cause, but occasionally, IV or subcutaneous immune globulin or, in patients with congenital immunodeficiency, stem cell transplantation is helpful.