Quinine Sensitivity: A New Cause of the Hemolytic Uremic Syndrome

In this issue of Annals, Maguire and coworkers [1] describe two patients who had symptoms and laboratory findings consistent with the adult hemolytic uremic syndrome of acute onset. In addition to the expected findings of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure, both patients had neutropenia and low-grade disseminated intravascular coagulation. One patient had a similar episode about 2 years earlier, and the other reported many previous episodes. The initial histories that the patients gave failed to identify exposure to medications. However, the urine of one patient contained quinine, the probable source of which was tonic water, and circumstantial evidence suggested that the second patient had taken quinine to prevent nocturnal leg cramps. Quinine was also implicated by the finding of quinine-dependent antibodies reactive with platelets, granulocytes, and erythrocytes in the serum of both patients. Clearly these patients had quinine-induced hemolytic uremic syndrome, a recently described syndrome [2] that can occur with or without associated disseminated intravascular coagulation or granulocytopenia [3, 4].

Many mechanisms have been implicated in drug-induced blood dyscrasias and tissue damage [5]. When peripheral destruction of cellular elements of the blood occurs, the cause is usually a peculiar type of immunoglobulin that, although harmless in itself, binds avidly to certain glycoproteins expressed on blood cells in the presence of the sensitizing drug [6]. Hundreds of drugs can induce such antibodies, but quinine and its diastereoisomer, quinidine, appear to do so more often than other agents. Only a small percentage of patients taking quinidine and quinine have this sensitivity, and there is no way to identify susceptible individuals. Although platelets are the preferred target for drug-induced antibodies, granulocytes, erythrocytes, and probably other tissues [7-9] are sometimes affected. Patients usually recover spontaneously when the provocative drug is withdrawn.

The mechanism by which drugs promote selective binding of these immunoglobulins to target glycoproteins is not fully understood, but evidence suggests that the inciting medications bind reversibly to specific protein domains to form complexes or to induce conformational changes (neoantigens) for which the antibodies are specific [5, 10, 11]. Why acute renal failure should develop in some patients with quinine-induced antibodies is unclear because intravascular hemolysis is generally not severe. Stroncek and colleagues [4] have suggested that the binding of immunoglobulins to granulocytes causes them to adhere to the microvasculature of the kidneys to produce renal dysfunction. Neahring and coworkers [12] have identified immunoglobulin (Ig)G and IgM antibodies reactive with endothelial cells in patients with quinine-induced hemolytic uremic syndrome and have suggested that antibody-mediated injury to endothelium may be responsible.

Maguire and associates raise several important points: Drug sensitivity should be suspected in any adult with acute-onset hemolytic uremic syndrome or thrombotic thrombocytopenic purpura, especially when associated with renal insufficiency. From the cases described in their article, it is apparent that this holds true even when the patient has no history of drug exposure. In my own clinical experience, I have found it remarkable how often patients with drug-induced thrombocytopenia deny drug exposure, especially during the acute phase of their illness. With respect to quinine, clinicians should keep in mind that this drug is present in soft drinks, aperitifs, and various over-the-counter medications and that sensitivity reactions can be induced by quinine in each of these forms.

The authors also raise the question of whether quinine in tablet form should be dispensed by prescription only. The most common use of quinine in tablet form is for the prevention of nocturnal muscle cramps, which can be distressing to susceptible individuals, especially the elderly. In the past, it has been questioned whether quinine is even effective for this purpose. Several recent clinical trials, however, have shown that the drug does, in fact, substantially reduce the frequency of such symptoms [13-16]. It can therefore be argued that quinine should remain available for this therapeutic indication. Limiting quinine tablets to prescription would, of course, not influence the exposure of millions of persons annually to quinine contained in beverages. The latter exposure is undoubtedly much more common than exposure to quinine in tablet form.

Most severe quinine side effects appear to be associated with ingestion of quinine tablets. This suggests that the larger dose of quinine contained in tablets (about 250 mg) is more likely to induce sensitivity, or at least to produce serious consequences, than the smaller amounts contained in, for example, tonic water (about 15 mg per bottle). Unfortunately, no animal model of drug sensitivity is available in which to study dose-response relationships in the induction of quinine sensitivity. Given that quinine is widely available to the public, studies to determine the frequency with which this compound causes substantial side effects seem to be indicated.

• Copyright 2004 by the American College of Physicians