Agranulocytosis iatrogenic


Agranulocytosis is defined as the complete absence of circulating neutrophils. One group this term as severe neutropenia (neutrophil o 0.3 x 109 / L), exposing themselves to infectious complications. The World Health Organization defines a grade IV neutropenia when the number of neutrophils is less than 0.5 x 109 / L. Acute agranulocytosis have mostly a drug-induced. They are reversible and their prognosis, related to infectious complications, is enhanced by a well conducted resuscitation. However, this is a medical emergency because of the risk of lightning systemic infection. Excluded from this study, cases involving multiple hematopoietic lineages cytopenias, severe neutropenia but predictable linked to cancer chemotherapy.


Drug-induced agranulocytosis:

Among the toxic haematological accidents, they are the most frequent. However, they are uncommon (a bit less than 5 cases per million population per year). There is a very important individual susceptibility and cases are mostly female. Many families of drugs have been incriminated. Their inventory is not final and we must be attentive to any new toxicity, often detected through pharmacovigilance centers. Drug agranulocytosis within two possible mechanisms without a mechanism to always be clear for a given drug or invariably involved for the same medicine (See: Further Reading).

1- immunological mechanism:

This mechanism is probably the most frequently involved. The adverse drug is independent of the dose. It requires a prior contact with the drug, the accident never occurring after a first introduction. The time between first contact and reintroduction does not matter (after a period of 8-10 days required for the synthesis of antibodies). When rechallenge, the disappearance of neutrophils is fast within hours. A genetic factor is involved and it has been shown in some cases of agranulocytosis immunological association with certain HLA haplotypes (human leukocyte antigen) class II.

2- toxic mechanism:

Here, the toxicity is dose dependent, occurring during prolonged treatment with progressive worsening during continued treatment. A second administration of the drug will not cause toxicity if the doses are lower, but will be new toxic when larger doses are reached. There is individual susceptibility (ie sensitivity of medullary progenitors drug that could be a latent defect, a drug metabolism disturbance that increases its toxicity). The table shows the main drugs for which a liability is recognized. Most of these drugs can toxicity on other hematopoietic lineages (platelet in particular).

Positive diagnosis:

A- Clinical signs:

The onset is sudden, occurring 8-15 days after the start of treatment or immediately involved in a new administration in the case of an immunological mechanism. However, in the case of a toxic mechanism, the signs can appear much longer after drug exposure.

1- Infectious Syndrome:

This is the clinical dominant element. High fever (> 38 ° C), with chills, tachycardia, sometimes associated with an inaugural shock. Some specific locations are infectious: oropharyngeal locations (tonsils, soft palate), gums (aphthous ulcerative necrotic lesions), severe digestive candidiasis, pulmonary homes systematized, perineal locations can be associated with extensive cellulitis. Others are not unique to agranulocytosis: urinary tract infection, skin infection. Compared to a non-neutropenic subject, the clinical expression is altered in patients with severe neutropenia: the local signs are moderate general signs are increased. Isolated fever without localized CIP is the most common expression of infection early. It can also be an expression of bacteraemia or severe visceral infection threatening the patient’s life.

2- Clinical examination:

The review did not show hepatosplenomegaly, sometimes inflammatory lymph nodes next to an infected site (ear, nose and larynx, for example).

B- haematological signs:

1- Complete blood count:

White blood cells are reduced, usually below 2 x 109 / L. Neutrophils are less than 0.3 x 109 / L (the absolute value of the number of neutrophils that is taken into account). The rest of the leukocyte count showed a majority of lymphocytes, some monocytes, sometimes a discrete eosinophilia (reflecting an allergic reaction). There are no circulating abnormal form. Hemoglobin and platelets are typically normal but quite frequently is moderate anemia or thrombocytopenia.

2- Myelogram:

Medullary cellularity is normal or slightly decreased. There is no abnormal cell. Achieving grainy line is elective: either total lack of granular elements or blocking maturation at an early stage (myeloblast-promyelocyte) or later (myelocyte-métamyélocyte) with excess elements at this stage and no Granular Surfacing beyond. There is a lympho-plasmocytosis sometimes considerable macrophages. The erythroid and megakaryocytic lineages are normal.

C- paraclinical exams:

• The imaging tests (X-ray, ultrasound, CT) are often little talking at the beginning of the infection. A chest radiograph should be systematic.

• Endoscopic exams are invasive techniques to high risk of infection and their indications are limited.

• Bacteriological samples are needed to clarify the nature of the infectious agents involved: repeated blood cultures, local levies [ENT, skin, mucous, urine, cerebrospinal fluid (CSF) …]

Their results are not expected for the initiation of treatment but will be useful for later adaptation of antibiotic therapy.Gram positive bacteria infections are the most common, accounting for over 60% of microbiologically documented infections: Staphylococcus coagulase negative Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus.Infections with Gram negative organisms are mainly of endogenous origin (Escherichia coli, Klebsiella, Pseudomonas). Pseudomonas are the most fearsome germs. Fungal infections (Candida) are seen during prolonged neutropenia and in immunocompromised patients. Despite the repetition of bacteriological samples, the proportion of febrile episodes documented in severe neutropenic patients is only 25%.

Differential diagnosis:

A- On the aspect of bone marrow aspiration:

It may exceptionally discuss:

– Acute promyelocytic leukemia, myeloid or to an excess of young cells;

– Refractory anemia with excess blasts;

– A Waldenstrom’s disease or myeloma on an important lymphocytes and plasma cells or plasma cells.

B- Discussion with other severe neutropenia:

– Chemo-induced, and always expected toxicity associated with the other lines.

– Viral: infectious mononucleosis, cytomegalovirus, parvovirus B19, viral hepatitis, HIV.

– Bacterial: typhoid, brucellosis, tuberculosis, bacterial sepsis.

– Parasitic: visceral leishmaniasis.

– Other neutropenia only rarely reach the stage of agranulocytosis.

Scalable diagnosis and severity of diagnosis:

A- Evolution:

Agranulocytosis is a transient condition. The haematological recovery is between 3-15 days depending on the degree of bone marrow involvement, exceptionally more. The recovery of neutrophils will be in a few days when rich marrow, with grainy maturation blocking. It will be longer in case of hypoplasia of the grainy line. The recovery is manifested by an increase of monocytes, followed, 48 hours later, neutrophils. A regenerative period with neutrophilic leukocytosis, and myelemia increase in platelets of normal. When the direct toxic mechanism is involved, it often persists after hematological recovery residual damage evidenced by a decrease in the cloning of spinal cord GM-CFC compared to a normal subject.

B- Morbidity and Mortality:

They are clearly linked to the speed of granular recovery, so the prognosis is associated with the risk of infection.This depends on:

– The duration of agranulocytosis. It can be evaluated from the myelogram. In case of total absence of gritty line, agranulocytosis lasts 15 days. If maturation locking repair is faster. But the drug prevents further repair;

– The conduct of anti-infectious resuscitation which has reduced mortality;

– The existence of factors favoring infection: mucocutaneous lesions, central venous, chronic pulmonary disease, chronic uropathy;

– The existence of associated factors that can complicate the picture: age, history of cardiovascular disease, kidney failure, malnutrition, dehydration and low blood pressure, diabetes, liver failure, immune deficiency with lymphopenia. Overall, the mortality rate is around 7%.

Etiologic diagnosis:

A- etiological survey:

The interrogation attempts to demonstrate drug toxicity, indicating the habitual or occasional drug dosages, including some regarded as harmless by the patient. The precise chronology of the drug compared to the onset of clinical signs is important. The origin is rarely evident with only one potentially toxic drug, known to the patient. Selective diagnosis is usually difficult to many drug taken and assistance may be provided by pharmacovigilance centers that indicate accountability for each drug taken by the patient.

B- biological tests:

The evidence of the responsibility of a drug are often difficult to obtain. They may be made by biological tests which are not practiced routinely but for which it is advantageous to freeze the serum of the patient in the acute phase for further studies.

• serum antibodies directed against antigranulocytaires Search healthy neutrophils, immunofluorescence (GIFT: granulocyte immunofluorescence test) by immunoassay (CELIA: competitive enzyme linked immunosorbent assay, or MAIGA: monoclonal antibody immobilization of granulocytic antigen) in leucoagglutination, in granulocytotoxicité.

• Culture granular progenitors in semisolid medium:

– GM-CFC cloning spinal cord of a normal control in the presence of patient serum acute phase of drug and complement;

– GM-CFC cloning spinal cord of a normal control in the presence of patient serum acute phase compared with serum from an individual treated with the same drug;

– GM-CFC cloning of the patient after bone marrow hematological recovery in the presence or absence of drug.Inhibition of cloning GM-CFC in the presence of drug, regardless of the addition of serum acute phase is in favor of a direct toxic mechanism. Inhibition in the presence only of the serum of the patient’s acute phase is in favor of an immunological mechanism.


All but essential drug should be discontinued. Any drug supposedly toxic and need to be replaced by a drug whose safety is recognized.

A- Infection Prevention, hygiene and surveillance measures:

– Private Room Isolation.

– Exclusive Administration cooked food.

– Health care: patient’s careful toilet, antiseptic mouthwashes, hand washing before and after patient contact, wearing bib, gown, shoe covers, gloves for care.

– Clinical monitoring, regular intake temperature.

– Systematic bacteriological samples (blood cultures, nose, pharynx, rectum, urine) and directed by symptoms.

– Monitoring the chest radiograph.

– Antibiotic prophylaxis: the administration of ciprofloxacin can prevent infections with Gram negative organisms. The addition of a penicillin or a macrolide allows prevention of Gram-positive infections. The administration of an antifungal (fluconazole) can be offered to high-risk individuals without a benefit has been demonstrated in primary prophylaxis.

B- Treatment of infection:

In case of fever and (or) symptomatic outbreaks, antibiotic prophylaxis is replaced by an empirical curative broad spectrum antibiotics administered intravenously. This antibiotic will be undertaken before any bacteriological documentation and must involve unless cons-indication, a penicillin or cephalosporin and an aminoglycoside 3rd generation. It should be immediately effective on Gram negative bacteria including Pseudomonas aeruginosa. It may be guided by clinical signs: erysipelas, boils evoke a Gram-positive (Staphylococcus, Streptococcus), urinary or anal location evokes a Gram negative (Enterobacter, Pseudomonas). Serum bactericidal levels should be higher than for a favorable trend in the non septicemia in neutropenic subject. The preferred choice usually associate ticarcilline- clavulanic acid, piperacillin-tazobactam, ceftazidime, cefepime, imipenem-amikacin or cilastin + isepamicin. A second-line treatment will be considered after 48-72 hours for evaluation of the clinical situation and in view of bacteriological results. If the clinical response is good, the initial treatment is continued. If signs of infection persists, is added a glycopeptide (vancomycin, teicoplanin) in the presence of a Staphylococcus or other Gram-positive and adapt treatment to the antibiogram. The failure of appropriate antibiotic therapy or absence of bacterial isolation is considered an antifungal treatment with amphotericin B. The use of granulocyte growth factors accelerates the haematological recovery, reduce fatal complications, decrease duration of antibiotic therapy and hospitalization. The G-CSF (granulocyte colony stimulating factor) recombinant (Granocyte, Neupogen) is preferred GM-CSF (granulocyte macrophage colony stimulating factor) for its better tolerance. The standard dose is 5 mg per kg per day, subcutaneously, to correct the figure of polymorphonuclear. A short curing 5 to 7 days is usually sufficient, resulting in rapid response and immediate resolution of infectious signs. Possible side effects of G-CSF are headache, myalgia, bone pain, responding to paracetamol. Thrombocytopenia and transient lymphopenia can be.

C- Prevention of recurrence:

In any patient with agranulocytosis, the causal drug is definitely not recommended and any specialty container. Any reintroduction (in the case of an immuno-allergic phenomenon) regardless of dose and in any form whatsoever, lead again to agranulocytosis. We must give the patient a list of specialties. It is better to avoid any medicine which can cause a hematopoietic toxicity.

Highlights to include:

Bacterial infection is the major risk for severe neutropenia. Healing depends exclusively on the antibiotic treatment that is no longer powered by the phagocytic function of polymorphonuclear.

• The prognosis of infection is determined by the depth and duration of neutropenia.

• Fever is often the only sign of infection, neutropenia responsible for a typical attenuation of local signs. Infection with gram-negative bacilli, especially Pseudomonas aeruginosa can be fulminant.

• The G-CSF, although expensive, is justified because the accelerated hematopoietic recovery reduces mortality and length of hospital stay. By cons, it is not indicated in the absence of infection.

• In vitro tests rarely possible to conclude that the responsibility of a drug. They are often made with the native and false negatives drug can be linked to the immunogenic activity of a metabolite of the drug.

Strong Points to remember:

The risk of infection is severe when the number of neutrophils is less than 0.5 x 109 / L, it is important when agranulocytosis extends beyond 7 days.

• Local infectious signs are often moderate. General symptoms are usually increased. A fever of unknown origin is a common table. The major risk is that of a Gram negative septic shock. • The infection is microbiologically documented in 25% of cases.

• An empirical broad spectrum antibiotic therapy should be carried out urgently, from the bacteriological samples taken.

• It will eventually be adapted in case of persistent infection at 48 hours.

• The drug in question is sometimes difficult to identify, especially in polymedicated subjects.

• After haematological recovery, the drug in question should be permanently outcast.


Mechanisms Drug agranulocytosis within two possible pathophysiological mechanisms, immunological or through direct toxicity. Usually, however, the precise mechanism by which a drug cause agranulocytosis is unknown and the factors that could cause patient education are not known. A patient may have consumed the drug for months or years before agranulocytosis. Immunological mechanism The mechanism is shown for amidopyrine, diclofenac, penicillins, antithyroid drugs, antimalarials, levamisole, chlorpropamide, clozapine. The drug may act in several ways.

• Acting as a hapten (Fig. 1), the drug can bind to the membrane of polynuclear induce the formation of antibodies against this antigenic become complex. These antibodies are responsible for the lysis of target cells carrying the drug.

In the hapten-type mechanism, the drug binds to the target cell, there is antibody production and destruction by such antibodies carrier of the drug cells.
In the hapten-type mechanism, the drug binds to the target cell, there is antibody production and destruction by such antibodies carrier of the drug cells.

• The drug may induce the formation of antibodies (Fig. 2), the two forming a immune complex which adsorbs onto the membrane of granulocytes and causes cell lysis by complement activation. This mechanism is considered to be the most commonly involved.

There is formation of an immune complex with the antibody-drug-induced, adhesion of immune-complex to the target cell and destruction of the target cell.
There is formation of an immune complex with the antibody-drug-induced, adhesion of immune-complex to the target cell and destruction of the target cell.

• Finally, the drug can alter the membrane of neutrophils, inducing the formation of autoantibodies (Fig. 3) which will destroy the target cells in the absence of the drug. This lytic activity is exerted on the circulating compartment, possibly on granular medullary precursors sharing the same antigenic determinants that circulating granulocytes.

In autoimmunity, the drug induces an autoantibody and the target cell is destroyed by the antibody in the absence of the drug.
In autoimmunity, the drug induces an autoantibody and the target cell is destroyed by the antibody in the absence of the drug.

Outside the quinine-dependent antibodies, specific structures granulocytes recognized by drug-dependent antibodies were not identified. Direct toxic mechanism This mechanism is shown to phenothiazines, phenylbutazone, carbamazepine, gold salts, cimetidine. The infringes on myeloid stem cells, and a moderate toxicity on other lines, megakaryocytic and erythroid, may be. Neutropenia was more common than agranulocytosis which is the extreme outcome. An abnormal metabolism of the drug leads to a toxic level of drug or its metabolites for granular progenitors.