Amodiaquine-induced agranulocytosis: report of a case with in vitro studies of granulocyte-macrophage progenitor cells

We report a case of amodiaquine-induced agranulocytosis in a 60-year-old woman. Four months after the agranulocytosis episode we investigated the effect of the drug using in vitro agar culture techniques. Amodiaquine at increasing concentrations (0.005, 0.05 and 0.5 microgram/ml) displayed an inhibitory effect, probably dose-dependent, on the growth of the patient's bone marrow GM-CFU colonies in the absence of autologous serum. In contrast, no effect was found on the colony and cluster growth of bone marrow samples from 13 healthy controls. Though it has been shown in several cases that amodiaquine-induced agranulocytosis occurs via immune-mediated mechanisms, our data are in support of a direct toxic effect of the drug on abnormally sensitive myeloid progenitor cells.     

Amodiaquine-induced fulminant hepatitis

Three patients suffered from fulminant hepatitis within 23, 59 and 22 weeks after having ingested a total dose of 16, 26 and 15 g, respectively, of amodiaquine for the prophylaxis of malaria. Amodiaquine administration was continued for 44, 21 and 25 days after the onset of jaundice, respectively. One patient underwent emergency orthotopic liver transplantation and survived. The other two died. Fulminant hepatitis threatens patients in whom amodiaquine administration is protracted for several months and not interrupted when jaundice occurs.     

Amodiaquine-induced hepatitis. A report of seven cases

Seven patients developed hepatitis after receiving amodiaquine for malaria prophylaxis for 4 to 15 weeks. Four patients had a minor form of hepatitis: jaundice was mild or absent, serum aminotransferase levels were moderately increased, and recovery was prompt. Three patients had a severe form: jaundice was intense, serum aminotransferase levels were markedly increased, jaundice persisted for 3 to 6 months, and liver tests were still abnormal 7 to 27 months after the onset of hepatitis. In two patients, serum aminotransferase levels increased promptly after readministration of the drug, which is consistent with an immunoallergic mechanism for amodiaquine-induced hepatitis.     

Quinidine-induced agranulocytosis

A case of agranulocytosis in an 86-year-old man after 8 weeks treatment with quinidine sulfate is described. Acute phase serum from the patient demonstrated antineutrophil activity by the microgranulocytotoxicity assay. Review of the literature reveals that more than one mechanism could cause this idiosyncratic immune-mediated agranulocytosis.     

Toenails and agranulocytosis

The objective of this article was the study of 12 cases of granulocytopenia associated with terbinafine use in Australia, the most recent, with agranulocytosis, which is described in detail. The mean age of the participants was 64 years (range 35-79 years). Sex was reported in 11 patients and all but one was a woman. Time to onset of neutropenia/agranulocytosis was 4-5 weeks in most cases. Neutropenia was typically severe with neutrophil counts < or = 0.3 x 10(3)/mm3 in all but 3 of 11 patients where counts were given. Terbinafine was stopped in all patients, five were hospitalized and one died of septic shock. Six patients received antibiotics and three were given granulocyte colony stimulating factor. Terbinafine, indicated for the treatment of onychomycosis and ringworm, may rarely be associated with granulocytopenia, which is typically severe. It takes approximately 1 month or longer for the development of manifestations of neutropenia, which include fatigue, fever, sore throat and mouth ulceration. Withdrawal of terbinafine and appropriate management of febrile neutropenia will probably result in a favourable outcome. Patients should be warned about this potentially life-threatening adverse reaction and the warning symptoms.     

Severe antibody-mediated agranulocytosis

A 56-year-old female with Crohn's disease was admitted to the hospital with malaise, fever, and a low white blood cell count (0.8 x 10(9)/l) with no granulocytes or myeloid precursor cells in the bone marrow. The leucopenia was initially thought to be the result of an infection and she was treated with antibiotics and granulocyte colony-stimulating factor (G-CSF, filgrastim). However, the bacterial cultures and viral tests were all negative. The patient's condition deteriorated and she became morbidly ill, but recovered after high dose steroid treatment. Six weeks later she relapsed whilst receiving 7.5 mg daily dose of prednisolone. She recovered quickly after being given high dose methylprednisolone in combination with filgrastim. A high maintenance dose of prednisolone was tapered over 5 months. She has not relapsed since and is currently well. Antibodies to the human neutrophil antigen (HNA)-3a were detected, but these antibodies could not easily explain her agranulocytosis as she had a HNA-3a negative phenotype. It seems plausible that her agranulocytosis was immune mediated through autoantibodies directed towards the early myeloid cells.     

Idiosyncratic drug-induced agranulocytosis

BACKGROUND: Agranulocytosis is a life-threatening disorder that frequently occurs as an adverse reaction to drugs. CURRENT DATA: Idiosyncratic drug-induced agranulocytosis is characterized by a neutrophil count <0.5x10(9)/l, in serious forms <0,1x10(9)/l that currently occurs especially in association with antibiotics, antithyroid drugs ant ticlopidine (>60% of the incriminated drugs). The overall incidence of idiosyncratic agranulocytosis ranges from 2.4 to 15.4 cases per million patients exposed to drugs per year. Although patients experiencing idiosyncratic agranulocytosis may be asymptomatic (50%), the severity of the neutropenia usually leads to severe sepsis: fever of unknown origin, septicemia, septic shock or localized documented infections such as sore throat, various cutaneous infections or pneumonia. Nevertheless, the mortality rate of idiosyncratic agranulocytosis is now around 5% with appropriate management. PERSPECTIVES: In the future, management of drug-induced agranulocytosis may include pre-established procedures using in critically situations, broad-spectrum antibiotic therapy and hematopoietic growth factors (G-CSF).     

Population-based drug-induced agranulocytosis

BACKGROUND: Since the publication of a major international case-control study on the risk of agranulocytosis associated with the use of medicines in the 1980s, many new drugs have been introduced in therapeutics. METHODS: Seventeen units of hematology contribute to the case-control surveillance of agranulocytosis and aplastic anemia in Barcelona, Spain. After a follow-up of 78.73 million person-years, 177 community cases of agranulocytosis were compared with 586 sex-, age, and hospital-matched control subjects with regard to previous use of medicines. RESULTS: The annual incidence of community-acquired agranulocytosis was 3.46:1 million, and it increased with age. The fatality rate was 7.0%, and the mortality rate was 0.24:1 million. The drug most strongly associated with a risk of agranulocytosis was ticlopidine hydrochloride with an odds ratio (OR) of 103.23 (95% confidence interval [CI], 12.73-837.44), followed by calcium dobesilate (OR, 77.84 [95% CI, 4.50-1346.20]), antithyroid drugs (OR, 52.75 [95% CI, 5.82-478.03]), dipyrone (metamizole sodium and metamizole magnesium) (OR, 25.76 [95% CI, 8.39-179.12]), and spironolactone (OR, 19.97 [95% CI, 2.27-175.89]). Other drugs associated with a significant risk were pyrithyldione, cinepazide, aprindine hydrochloride, carbamazepine, sulfonamides, phenytoin and phenytoin sodium, beta-lactam antibiotics, erythromycin stearate and erythromycin ethylsuccinate, and diclofenac sodium. Individual attributable incidences for all these drugs, which collectively accounted for 68.6% of cases, were less than 1:1 million per year. CONCLUSIONS: Agranulocytosis is rare but serious. A few drugs account for two thirds of the cases. Our results also provide reassurance regarding the risk associated with a number of newly marketed drugs.