Drug-induced eosinophilia

Eosinophils are a type of white blood cell formed in the bone marrow from stem cells. They are granulocytes derived from the same progenitor cells as monocytes, macrophages, neutrophils and basophils. The usual blood eosinophil count is 350 per mm³ with diurnal variation; the peak occurs at night and the trough in the morning. The circulating half-life of most eosinophils is six to 12 hours with most eosinophils residing in tissues (eg, the upper respiratory and gastrointestinal tract).¹

There are a number of hypotheses regarding the function of eosinophils. It has been suggested they modulate the intensity of immunoglobulin E (IgE) and IgG-mediated reactions, for example, in schistosomiasis.² They are toxic to helminths in vitro and it is also possible that eosinophils protect against certain tissue invasive metazoan parasites such as Pneumocystis carinii.^1,3 Finally, they may act via hormones such as adrenaline, oestrogens or glucocorticoids.³

Eosinophilia is defined as a peripheral blood eosinophil count greater than 350 per mm³.¹ (Hypereosinophilia is defined as a peripheral blood count greater than 1,500 per mm³.) It is a common allergic manifestation of many drugs and usually disappears when the drug is stopped. Unless very severe, the severity of eosinophilia is solely related to the allergic responses that accompany it. The parts of the body that tend to be affected are the heart, lungs, skin, joints, gut and central nervous system. Prolonged periods of eosinophilia may result in tissue damage although the exact mechanism by which this occurs is still unclear.¹

There are a number of causes of eosinophilia, allergic and atopic diseases being among the most common.¹ Infections, particularly parasitic infestation, may produce an eosinophilia, as may fungal infections. Generally, however, bacterial or viral infections are associated with eosinopenia.⁴ Neoplastic disease, for example Hodgkin’s disease, may occasionally cause an elevated eosinophil count.³ Connective tissue disorders and skin disorders, such as pemphigus, are often associated with eosinophilia.¹

The eosinophilic pneumonias are a group of diseases of both known and unknown aetiology, characterised by eosinophilic pulmonary infiltration and peripheral blood eosinophilia. Simple pulmonary eosinophilia is known as Loeffler’s syndrome and may be associated with a low grade fever, minimal respiratory symptoms and prompt recovery.¹

Relating eosinophilia to a particular drug can be difficult. Hypersensitivity reactions to substances such as nickel, ragweed, pollen, poison ivy extracts, helminthic infestations, brucellosis, amoebiasis and coccidioidomycosis have all been associated with eosinophilia.⁵ To confirm a drug reaction, these chemical and infectious causes must be excluded. Diagnosis is further complicated because the drug may worsen a pre-existing eosinophilia, particularly in an atopic patient.⁶ Given that allergic reactions may result in eosinophilia, it would appear to be a potential problem with many drugs, as dictated by the idiosyncratic response of the individual patient.

This paper concentrates on drugs that are reported to produce serious reactions, rather than mild or self-limiting drug induced eosinophilia. Drugs associated with eosinophilia are outlined in Table 1.

Anti-infective agents

Antimalarials 

There are case reports of pulmonary eosinophilia in three patients taking pyrimethamine-dapsone (Maloprim; Wellcome) and in one patient taking pyrimethamine-chloroquine (Daraclor; Wellcome).⁷ In two of these cases a lung biopsy confirmed pulmonary eosinophilia. Rechallenge with Maloprim by the patient in one case had near fatal results. Pyrimethamine was the common drug in all four cases, so the authors concluded that pyrimethamine may cause eosinophilia.

There is a case report of pulmonary eosinophilia (Löffler’s syndrome) associated with dapsone usage.⁸ The patient recovered, but the authors recommended the eosinophil count should be carefully monitored in patients receiving dapsone.

Penicillins 

Penicillins are commonly quoted as causing eosinophilia.^4,9,10 However, few case reports could be found, suggesting the eosinophilia is usually mild and transient. Penicillin-induced eosinophilia has been reported associated with nephropathy and interstitial nephritis.¹¹ Eosinophiluria may also be present.

Penicillin therapy has been reported to cause eosinophilia with a fever and a maculopapular rash.¹² There has been a report of the potentially fatal condition of toxic epidermal necrolysis.¹³ Fever and eosinophilia were also noted.

Penicillins have also been implicated in causing the potentially fatal condition of hypersensitivity myocarditis, with presenting symptoms of fever and rash.¹⁴

Cephalosporins 

The incidence of eosinophilic reactions in patients taking cephalosporins is quoted as approximately 8 per cent.¹⁵ There are, however, few reports in the literature, suggesting, therefore, that cephalosporin-induced eosinophilia, like penicillin-induced eosinophilia, is usually mild and transient.

There are two cases of a peripheral blood eosinophilia and hematuria in two patients treated with high-dose cephalexin (20–24g daily).¹⁶ In one case the symptoms included a fever, maculopapular pruritic discharge and a generalised lymphadenopathy. In both cases symptoms resolved once cephalexin was discontinued, but, unfortunately, rechallenge could not be carried out.

Cephalexin has also been reported to cause pulmonary eosinophilia.¹⁷ A patient developed a diffuse maculopapular rash seven days after commencing cephalexin therapy (500mg three times a day). Eosinophilia and diffuse consolidation of both lungs were noted. The patient made a complete recovery after prednisolone therapy and discontinuation of cephalexin.

There is a reported case of cephalosporin therapy associated with peripheral eosinophilia, pericarditis and eosinophilic cholecystitis.¹⁵ This resolved rapidly when cephalosporin therapy was discontinued. The authors concluded that although a rechallenge would be necessary to confirm hypersensitivity, the close temporal association suggests that the cephalosporin caused the eosinophilic cholecystitis and pericarditis.

Ciprofloxacin 

There is a case report of eosinophilic meningitis associated with ciprofloxacin administration.¹⁸ Five days after a course of ciprofloxacin (500mg twice a day) had been commenced, the patient presented with fever and neck pain. The patient’s peripheral white blood cell count was 6,700/mm³ with 6 per cent eosinophilia. The lumbar puncture revealed 147 white blood cells with 24 per cent eosinophils; the rest were mononuclear cells. Cytologic examination of the spinal fluid confirmed the presence of large numbers of eosinophils, but showed no malignancy. Following supportive treatment the patient made a full recovery. The authors stated that eosinophilic meningitis is very uncommon and is only rarely caused by drugs, but they concluded in this case the most likely diagnosis was eosinophilic meningitis caused by ciprofloxacin therapy.

Glycopeptide antibiotics 

Vancomycin has been reported to cause a delayed hypersensitivity reaction with eosinophilia, and symptoms such as a delayed cutaneous eruption; interstitial nephritis and fever are often present.^19,20 Although, usually, the patients are on multiple medication making the association less clear, there is one case in a patient on just vancomycin and warfarin.¹⁹ The patient had been receiving 1.75g of vancomycin intravenously as a single daily dose for four weeks, when fever, erythema multiforme, eosinophilia, and presumed interstitial nephritis were noted. 

The reaction resolved upon discontinuation of vancomycin and initiation of methylprednisolone therapy. As warfarin very rarely causes a hypersensitivity reaction, the authors suggested the most likely cause was the vancomycin.

Teicoplanin has been reported to cause a similar reaction of interstitial nephritis and eosinophilia, although fever and rash were not noted.²¹ Again the reaction was delayed: an elevated serum creatinine was first noted after 40 days of teicoplanin therapy. There was no resolution of the nephritis despite discontinuation of teicoplanin.

Sulphonamides 

Sulphonamides are among the best known drugs capable of causing pulmonary eosinophilia, which, in the 1940s, was commonly associated with sulphonamide antibiotics. It tended to occur 10–14 days after exposure and the symptoms included fever, blood eosinophilia and new pulmonary opacities. These rapidly disappeared after the sulphonamide was discontinued.²² Sulphonamides have also been associated with the development of hypersensitivity myocarditis.¹⁴

Tetracyclines 

While pulmonary eosinophilia has been reported following the administration of tetracycline,²³ it is more frequently associated with minocycline.

Minocycline-induced syndrome of pulmonary eosinophilia is characterised by pulmonary infiltrates on the chest roentgenogram, chest symptoms such as dyspnoea, and eosinophilia in blood and bronchoalveolar lavage fluids.²⁴ These presenting symptoms may be severe enough to lead to transient respiratory failure and require treatment with steroids. The outcome after minocycline has been discontinued is generally good and there have been no reports of fatalities.²⁵

Nitrofurantoin 

There are a number of reports of nitrofurantoin causing pulmonary disease with eosinophilia.^9,26 Nitrofurantoin is unique among drugs causing pulmonary eosinophilia, in that there is an acute and a chronic pattern.⁹ The acute episode, which tends to occur within one month of therapy, presents as a fever with cough and pulmonary infiltrates, and there is often a marked peripheral blood eosinophilia.⁹ These complications usually resolve within 15 days if nitrofurantoin is discontinued,²⁶ but continued therapy may lead to a chronic disease which is characterised by fibrosis.¹⁰ Other symptoms of the chronic disease, which is less common and tends to occur two months to five years after initiation of therapy, include an exertional dyspnoea and a non-productive cough.⁹ Nitrofurantoin should be stopped if this is suspected.⁹

Amphotericin B 

There is a case report describing eosinophilia and a generalised maculopapular rash as apparent manifestations of amphotericin B hypersensitivity.²⁷ The symptoms resolved following discontinuation of amphotericin B. After rechallenge, the rash rapidly reappeared, suggesting a strong association.

Antituberculous therapy 

There are a number of case reports of eosinophilia^28-31 in patients on antituberculous therapy. However, as patients are often on multiple drug regimens, it can be difficult to pinpoint the causative agent.

There is a case report of ethambutol-induced pulmonary infiltrates with eosinophilia and a skin reaction.²⁸ A woman aged 67 with tuberculosis was treated with streptomycin, isoniazid, rifampicin, ethambutol and pyrazinamide. After eight weeks of therapy she developed a blood eosinophilia with pulmonary infiltrates and a skin rash. Following rechallenge this was shown to be related to the ethambutol therapy.

Rifampicin has been reported to cause eosinophilia with both pulmonary and colitic complications.^29,30 There are also reports of eosinophilia occurring in the presence of other drugs.³¹

One patient developed a peak eosinophil count of 5,500/mm³ and bilateral pulmonary infiltrates.²⁹ The patient improved, and the eosinophilia disappeared within 18 days of stopping the rifampicin.

A case of eosinophilic colitis occurred in a patient started on quadruple therapy of ethambutol, rifampicin, isoniazid and pyrazinamide. Nine days after starting treatment she became pyrexial, and developed diarrhoea with the passage of fresh blood, nausea and vomiting with a colicky pain, and a generalised pruritic skin rash.³⁰ Blood counts failed to reveal a significant peripheral blood eosinophilia. Colonic biopsy specimens showed a chronic inflammatory cell infiltrate, which included plasma cells, macrophages and eosinophils.

Following treatment with rectal prednisolone and cessation of antituberculous therapy, the rash and abdominal symptoms resolved within six days. Each of the drugs was reintroduced in turn, and following rifampicin therapy, the abdominal symptoms and rash reappeared. After rifampicin had been discontinued, the symptoms resolved within four days and did not reoccur for a period of three months while the patient was on isoniazid, ethambutol and pyrazinamide. The authors concluded there was substantial evidence of a causal relationship between rifampicin and eosinophilic colitis.

Cardiovascular drugs

ACE inhibitors 

Eosinophilia is a frequent side effect during captopril therapy, but it rarely requires discontinuation of therapy. Dermal and pulmonary complications are most likely to require discontinuation, although some allergic reactions improve if the captopril dose is reduced.³² There is a case report of captopril causing pulmonary infiltration with eosinophilia.³³ The patient developed diffuse lung field infiltrates with a productive cough and a marked peripheral eosinophilia. The symptoms disappeared after captopril had been discontinued.

Enalapril has been reported to cause a pruritic rash associated with eosinophilia.³⁴ The rash resolved seven days after enalapril was discontinued. Cross-sensitivity did not appear to be a problem, as the rash was not noted when the patient was started on captopril.

There is a case of perindopril causing pneumonitis associated with bronchial wall eosinophilic infiltration.³⁵ The symptoms, which included fever, dry cough and dyspnoea, developed after the patient had been taking perindopril for six months. Following perindopril withdrawal and corticosteroid therapy, there was a marked clinical improvement. After rechallenge with a single perindopril tablet seven months later, fever, cough and dyspnoea reappeared.

Dermal and pulmonary complications of eosinophilia have been reported with at least three ACE inhibitors, and it seems likely this is a class effect. Clinicians should be aware of this. In one case, the diagnosis was confirmed by rechallenge.

Spironolactone 

There are two cases of spironolactone causing a severe eosinophilia with an erythematous macular rash.³⁶ In both cases, the rash developed within 12 hours of spironolactone being commenced, and withdrawal of the drug resulted in a slow resolution of the eosinophilia and rash. Although a rechallenge was not undertaken, the authors suggested that spironolactone caused the rash and eosinophilia via a type I allergic reaction.

Calcium channel blockers 

There is a case report of a patient who developed a fever, relative eosinophilia and a pruritic maculopapular rash following treatment with diltiazem.³⁷ The symptoms resolved once diltiazem had been discontinued; unfortunately, however, rechallenge could not be conducted.

Anti-arrhythmic drugs 

Eosinophilia has been reported with quinidine.¹¹ There have been rare reports of eosinophilia in patients taking cardiac glycosides, occasionally with a cutaneous reaction.³⁸

Methyldopa 

Methyldopa has been implicated in the potentially fatal condition of hypersensitivity myocarditis.³⁹ While a raised eosinophilia count is usually observed, the presenting symptom has included headache, malaise or nausea.¹⁴

CNS drugs

Antipsychotics 

Eosinophilia, which may be dramatic, is a reported side effect of chlorpromazine,^5,40 although it is often asymptomatic and disappears even if chlorpromazine therapy is continued.

There is one reported case of pulmonary infiltrations with eosinophilia that became apparent three weeks after chlorpromazine had been commenced. Symptoms included a fever and a non-productive cough.⁵ A chest X-ray showed streaky right lobe densities with a possible small pleural effusion, while the white blood cell count increased to 21,000/mm³ with 53 per cent eosinophils. After chlorpromazine was discontinued, the symptoms resolved and the eosinophil count gradually fell. Following rechallenge with chlorpromazine, the eosinophil count once again climbed.

Antidepressants 

Antidepressants are not commonly associated with eosinophilia. Occasionally a transient eosinophilia occurs with tricyclic antidepressants during the first few weeks of therapy, although this is not thought to be clinically significant.⁴¹ There are a few reports related to desipramine and imipramine,^42,43 and a case of eosinophilia and jaundice in a patient treated with amitriptyline.⁴⁴ There is also a case report of eosinophilic pneumonia (confirmed by bronchoalveolar lavage) and respiratory failure associated with trazodone overdose.⁴³

Tryptophan, which is used as an antidepressant and a dietary supplement, has been implicated in causing a potentially fatal eosinophilia-myalgia syndrome (EMS).⁴⁵ The characteristic features are a raised eosinophilia count (>2,000/mm³), severe myalgia, oedema and a rash.⁴⁶ However, other parts of the body, including the liver and the central nervous system, may be involved.⁴⁶

In patients who develop the syndrome, tryptophan should be discontinued. There is, however, usually only a gradual improvement. There have been a number of fatalities,⁴⁷ with ascending polyneuropathy with paralysis and respiratory failure cited as the main cause of death.⁴⁸ The syndrome is often chronic, with most patients reporting EMS to be having a major impact on their lifestyle 3.6 years after onset.⁴⁵ The main chronic symptoms of EMS are neurological and musculoskeletal.⁴⁹ The cause of the syndrome appears to be related to a contaminant in the bulk manufacturing process of a single Japanese company.⁴⁵

Anticonvulsants 

Phenobarbitone, carbamazepine and phenytoin have been implicated in severe, multisystem, potentially life threatening eosinophilic reactions, the incidence of which is approximately one in 1,000 to one in 10,000.⁵⁰ Symptoms include skin rash, fever, haematologic abnormalities (including eosinophilia), hepatotoxicity, lymphadenopathy and sometimes pneumonitis.⁵⁰ Cardiac complications have also been reported.^39,51

A case is described of a 13-year-old boy who died of uncontrollable cardiac dysrhythmias two months after the start of carbamazepine therapy.⁵¹ Eosinophilia was first noted 17 days after carbamazepine had been started and the symptoms, which mimicked scarlet fever, included fever, rash, conjunctivitis, hepatitis and myocarditis. When the myocardium was examined at autopsy, severe eosinophilic myocarditis was noted. The authors suggested a diagnosis of eosinophilic myocarditis should be considered if fever, rash and eosinophilia occur after carbamazepine has been commenced. A case of eosinophilic myocarditis has also been reported in a patient taking both phenytoin and carbamazepine.³⁹

There are also cases of phenytoin induced pulmonary eosinophilia,⁵² including a case of Loeffler’s syndrome⁵³ which may have been caused by phenytoin. In one case, the symptoms included fever, diffuse bronchical wheezing and both sputum and peripheral blood eosinophilia.⁵² The patient developed acute renal and hepatic failure, and also respiratory failure, which required mechanical ventilation in addition to high-dose corticosteroids. The patient fully recovered.

In the patient who developed Loeffler’s syndrome, the symptoms included elevated liver function tests, a skin rash with mucosal involvement and an elevated white blood cell count including eosinophilia and cervical lymphadenopathy. The syndrome developed weeks after phenytoin had been commenced and resolved on discontinuation. Concurrently, the patient had also been taking phenobarbitone. Similar symptoms developed after carbamazepine had been started, and the authors concluded there been had cross-sensitivity to carbamazepine.⁵³

Valproic acid has also been associated with a case of eosinophilic pleural effusion and a peripheral blood eosinophilia.⁵⁴ When valproic acid therapy was stopped, the pleural effusion and eosinophilia resolved, so the authors claimed an association.

Antirheumatic drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) 

A number of different NSAIDs have been reported to induce respiratory disease associated with eosinophilia,^55–57and it seems likely this is a class effect. The reported agents include naproxen, fenoprofen, sulindac, diclofenac, piroxicam, azapropazone and diflunisal.^55-57 One source states the most frequently implicated agents are naproxen and azapropazone.⁵⁵ Another source states the incidence of eosinophilia with pulmonary infiltrates is greater with naproxen than ibuprofen.⁵⁶ It is impossible to determine categorically which of the NSAIDs causes the greatest risk, because it is likely that the syndrome is under-reported. The most common symptoms and signs include fever, dyspnoea, cough, infiltrates on chest roentgenogram and an absolute peripheral eosinophilia.⁵⁶ Generalised rashes, malaise, a sputum eosinophilia, leukocytosis and an elevated erythrocyte sedimentation rate are also common.⁵⁵

If eosinophilic pneumonia develops, the causative NSAID should be withdrawn. Most patients recover within two weeks.⁵⁷ While the course of the syndrome is usually relatively benign, it has been reported to cause residual pulmonary fibrosis and there has been a death reported.⁵⁵

There is also a case of eosinophilic meningitis associated with ibuprofen therapy.⁵⁸ A patient presented with meningeal symptoms, including severe bifrontal headache, photophobia, nausea and a stiff neck, 48 hours after she had started taking ibuprofen 400mg orally three times a day. There was no eosinophilia in the peripheral blood, but the cerebrospinal fluid (CSF) showed a marked eosinophilic response. Ibuprofen was discontinued: the meningeal symptoms resolved, and repeated CSF examinations showed decreasing numbers of eosinophils. The authors concluded that the eosinophilic meningitis was drug induced, but the only way to confirm this would be rechallenge.

Indomethacin has been reported to cause an acute renal failure associated with eosinophilia.¹¹

Gold 

Routine gold therapy may lead to eosinophilia. One study found that 47 per cent of patients on intramuscular gold with a diagnosis of rheumatoid arthritis developed eosinophilia.⁵⁹ The most common manifestation of the eosinophilia was a dermal reaction. However, the authors note that eosinophilia does occur in patients with rheumatoid arthritis not treated with gold.

Another study found eosinophilia, which was usually mild, occurred in only 21 per cent of patients receiving intramuscular gold and 14 per cent of patients receiving oral gold.⁶⁰ A further study also suggested that eosinophilia, which occurred in 26 per cent of patients, was rarely associated with toxicity.⁶¹

Gold therapy has also been associated with both eosinophilia pulmonary disease and eosinophilic colitis.^59,62 In one case of eosinophilic colitis, the patient became asymptomatic after intramuscular gold therapy had been discontinued and treatment with cromoglycate commenced.⁶³

Gastrointestinal drugs

Histamine receptor antagonists 

Ranitidine has been reported to cause eosinophilic pneumonia.⁶⁴ A patient was admitted to hospital 25 days after 150mg of ranitidine twice daily had been started, with symptoms of facial oedema, dyspnoea and a non-productive cough. The peripheral white blood cell count was 7,660 per mm³ (with 13 per cent eosinophils).

Auscultation of the lungs showed diffuse bilateral expiratory sibilus and basal hypophonesis. A diagnosis of atypical pneumonia was suspected and treatment with antibiotics commenced. However, after three days, no evidence of an infectious disease could be detected and the patient’s condition was worsening. A diagnosis of hypersensitivity pneumonia was, therefore, suspected. The antibiotics and ranitidine were discontinued and treatment with prednisolone was started. The patient improved rapidly and within three days he was completely asymptomatic with a normal peripheral white blood cell count. The authors concluded that, although without rechallenge, it was impossible to completely prove a cause-effect relationship, it was likely that the acute eosinophilic pneumonia was a hypersensitivity reaction associated with ranitidine.

A case of thrombocytopenia and eosinophilia associated with ranitidine has been reported.⁶⁵ A raised eosinophilia count was first noted two weeks after ranitidine 300mg daily was initiated and resolved after it had been discontinued.

Cimetidine has also been reported to cause eosinophilia, which was confirmed by rechallenge.⁶⁶

Proton pump inhibitors 

Eosinophilia has been reported with both lansoprazole and omeprazole.^67,68 It is possible that this is a class effect, although the clinical presentation varied. A patient on omeprazole therapy presented with non-oliguric acute renal failure.⁶⁸ Eosinophilia and eosinophiluria appeared after one month of omeprazole therapy; fever and skin rash were not detected. A diagnosis of drug-associated interstitial nephritis was made. The renal failure and eosinophiluria resolved spontaneously when omeprazole was discontinued. Unfortunately, there was no record of whether the eosinophilia resolved. A rechallenge was not conducted.

There is a case of an eosinophilia and myalgia related syndrome to lansoprazole use.⁶⁷ A 50-year-old white woman developed myalgia seven days after lansoprazole was initiated. Both the myalgia and the eosinophilia that was noted later resolved 40 days after lansoprazole was discontinued. The patient also received prednisone therapy. The authors noted the patient fulfilled diagnostic criteria for both eosinophilia-myalgia syndrome and eosinophilia fasciitis. They concluded that although other causes could not be eliminated the time scale implicated lansoprazole. A rechallenge was not, however, conducted.

Aminosalicylates 

Sulphasalazine^22,69 and mesalazine⁷⁰ have been reported to cause eosinophilia with pulmonary complications. There is a case report of an eosinophilic pneumonia and skin rash in a 21-year-old man on sulphasalazine.⁶⁹ After the drug had been discontinued, and treatment with steroids started, the rash and pulmonary infiltrates completely resolved.

There is a report of a patient who developed shortness of breath nine months after oral mesalazine had been initiated.⁷⁰ Findings, such as a peripheral eosinophilia, a low grade fever and bilateral pulmonary infiltrates, were consistent with a diagnosis of eosinophilic lung disease. The patient made a complete recovery following steroid therapy and discontinuation of mesalazine.

Other drugs

Chlorpropamide 

Chlorpropamide, a sulphonylurea, has been reported to cause pulmonary disease with eosinophilic infiltration.⁷¹ Chronic eosinophilic pneumonia has also been described during chlorpropamide therapy.¹¹ In one case, when other symptoms included nausea, vomiting, pruritus, a maculopapular rash and elevated hepatic enzymes, the symptoms of dyspnoea and hypoxemia were so severe that artificial respiration was required.⁷²

Cholestyramine 

Cholestyramine has been reported to be associated with eosinophilia in a five-week old baby who had persistent diarrhoea.⁷³ The eosinophilia, which the report suggested was due to systemic absorption, appeared to be dose-dependent and not associated with any other abnormalities.

Heparin 

There have been rare cases of hypereosinophilia with positive rechallenge associated with heparin reported in the French literature.¹¹ From Spain there is a report of eosinophilia in a 66-year-old patient treated with enoxaparin at a dose of 40mg every day for seven days.⁷⁴

Management

If the eosinophilia is mild, transient and asymptomatic, there is no need to take action. If, however, the eosinophilia is more severe and producing symptoms, the most important management step is to discontinue any agent that may have caused the reaction.

Eosinophilia usually occurs within eight weeks of any medicine being started, so agents started in this period should be discontinued initially. Symptoms have been reported to develop up to five years after initiation of a medicine.⁹ Patients usually recover after the offending drug is withdrawn. It is also important to treat any renal, hepatic, pulmonary, CNS or any other complications of the eosinophilia.

Corticosteroids are often used, but there are no placebo controlled trials assessing their effectiveness and their role is not clear. Some sources suggest they have little benefit and no effect on outcomes,^56,70 while others suggest that they produce a more rapid response.^50,55 It has been suggested that corticosteroids should be reserved for more serious reactions.⁵⁵ Corticosteroids are sometimes not prescribed because of concern about an infection causing the eosinophilia.⁵⁷

There is also some debate about the dose required. There are reports of doses between 10–100mg prednisone being used.⁴¹ Generally, high doses tend to be used; for example, daily doses of 60–90mg of prednisone or prednisolone have been used to treat NSAID-induced eosinophilic pneumonia.^55,75 There are reports of 30–40mg daily of prednisone being used to treat the mainly pulmonary symptoms of minocycline- or tetracycline-induced eosinophilia.^23,76 In one case, there were persistent dermal complications which required more prolonged treatment with prednisone.²³

Additionally, there is no clear consensus on the duration of corticosteroid therapy. Most patients receive two to six weeks’ treatment, although much longer courses have also been recommended and used. It has been reported that stopping steroid therapy, particularly in patients with chronic eosinophilia, may result in relapse.⁷⁷ These patients sometimes require long-term corticosteroids.⁹

Intravenous methylprednisolone at a dose of 50mg daily has been used to treat the symptoms of eosinophilia.¹⁹ There is a report of high dose intravenous methylprednisolone (125mg every four hours) being used.⁵² There is, however, no evidence that methylprednisolone is more effective than oral corticosteroid therapy.

Immunosuppressive therapy, such as azathioprine, hydroxyurea and cyclophosphamide has also been recommended.^39,78 It has been suggested that hydroxyurea is particularly useful in life-threatening hypereosinophilia.³ Some sources, however, question the benefit of such agents.⁴¹ Antihistamines have also been used.¹²

There is also a report of oral sodium cromoglicate being used successfully to treat gold-induced eosinophilic enterocolitis.⁶³ The patient received 20mg four times a day for about six weeks.

Conclusion

Literature on drug-induced eosinophilia is sparse and mainly consists of individual case reports. It is often impossible to confirm whether the eosinophilia is truly drug induced because ethical and practical considerations make rechallenge unwarranted. It is also highly probable that the syndrome is misdiagnosed and under-reported.

The condition often appears to be a class effect, and the groups of drugs most commonly implicated include NSAIDs, antimalarials, anti-epileptics, some antibiotics and drugs for tuberculosis.

Of the more recently licensed drugs, both ACE inhibitors and proton pump inhibitors appear to be associated with eosinophilia. Although there are not many documented cases, dermal and pulmonary complications of eosinophilia have been reported with at least three ACE inhibitors, although cross-sensitivity may not occur. More data are required on proton pump inhibitor-induced eosinophilia.

The severity varies greatly; anticonvulsants appear to be associated with a potentially life threatening reaction. The organs most often affected appear to be the lungs and the skin, although the CNS, kidney, gastrointestinal system, heart and musculosketetal system can also be affected.

Awareness of this potentially fatal condition needs to be raised to ensure prompt diagnosis. If eosinophilia develops, treatment usually consists of withdrawing the probable causative drug. Corticosteroids are often used, but their role in the management of this condition is controversial.

References

1. Berkow R, Fletcher AJ. The Merck manual of diagnosis and therapy (16th ed). Rahway: Merck Research Laboratories, 1992.
2. Koda-Kimble MA, Young LY. Applied therapeutics: the clinical use of drugs (5th ed). Vancouver: Applied Therapeutics Inc, 1993.
3. Weatherall DJ, Ledingham JGG, Warrell DA. Oxford textbook of medicine (3rd ed). Oxford: Oxford University Press, 1995.
4. Wykoff RF. Eosinophilia. Southern Med J 1986;79:608-12.
5. Shear MK. Chlorpromazine-induced PIE syndrome. Am J Psychiatry 1978;135:492-3.
6. Benichou C. Adverse drug reactions. France:Wiley, 1992.
7. Davidson AC, Bateman C, Shovlin C, Marrinan M, Burton GH, Cameron IR. Pulmonary toxicity of malaria prophylaxis. BMJ 1989;297;1240-1.
8. Janier M, Guillevin L, Badillet AS. Pulmonary eosinophilia associated with dapsone (letter). Lancet 1994;343:860-1.
9. Lopez M, Salvaggio JE. Eosinophilic pneumonias. Immunol Allergy Clin North Am 1992;12:349-63.
10. Spry CJF. Eosinophilia and allergic reactions to drugs. Clinics in Haematology 1980;9:521-34.
11. Dukes MNG. Meylers side effects of drugs (13th ed). Oxford: Elsevier Press,1996.
12. Girard JP, Kunz ML, Kobayashi S, Rose NR, Arbesman CE. Penicillin hypersensitivity with eosinophilia. Am J Med 1967; 42:441-8.
13. Romano A, Di Fonso M, Pocobelli D, Giannarini L, Venuti A, Garcovich A. Two cases of toxic epidermal necrolysis caused by delayed hypersensitivity to beta-lactam antibiotics. J Invest Allergol Clin Immunol 1993;3:53-5.
14. Fenoglio JJ, McAllister HA, Mullick FG. Drug related myocarditis. Human Pathol 1981;12:900-7.
15. Felman RH, Sutherland DB, Conklin JL, Mitros FA. Eosinophilic cholecystitis, appendiceal inflammation, pericarditis, and cephalosporin-associated eosinophilia. Dig Dis Sci 1994;39:418-22.
16. Verma S, Kieff E. Cephalexin-related nephropathy. JAMA 1975;234:618-9.
17. Smith JH, Weinstein VF. Cephalexin associated pulmonary infiltration with circulating eosinophilia. BMJ 1987;294:776.
18. Asperilla MO, Smego RA. Eosinophilic meningitis associated with ciprofloxacin. Am J Med 1989;87:589-90.
19. Marik PE, Ferris N. Delayed hypersensitivity reaction to vancomycin. Pharmacotherapy 1997;17:1341-4.
20. Hannah BA, Kimmel PL, Dosa S, Turner ML. Vancomycin-induced toxic epidermal necrolysis. Southern Med J 1990;83: 720-2.
21. Frye RF, Job ML, Dretler RH, Rosenbaum BJ. Teicoplanin nephrotoxicity: First case report. Pharmacotherapy 1992;12: 240-2.
22. Feinmann L. Drug-induced lung disease: pulmonary eosinophilia and sulphonamides. Proc R Soc Med 1975;68: 20-1.
23. Ho D, Tashkin DP, Bein MF, Sharma O. Pulmonary infiltrates with eosinophilia associated with tetracycline. Chest 1979;76:33-6.
24. Sitbon O, Bidel N, Dussopt C, Azarian R, Braud ML, Lebargy F et al. Minocycline pneumonitis and eosinophilia. Arch Intern Med 1994;154:1633-40.
25. Dykhuizen RS, Zaidi AM, Godden DJ, Jegarajah S, Legge JS. Minocycline and pulmonary eosinophilia. BMJ 1995;310: 1520-1.
26. Sovijarvi ARA, Lemola M, Stenius B, Idanpaan-Heikkila J. Nitrofurantoin induced acute, subacute and chronic pulmonary reactions. A report of 66 cases. Scand J Resp Dis 1977;58:41-50.
27. Lorber B, Cutler C, Barry WE. Allergic rash due to amphotericin B (letter). Ann Intern Med 1976;84:54.
28. Wong PC, Yew WW, Wong CF, Choi HY. Ethambutol-induced pulmonary infiltrates with eosinophilia and skin involvement. Eur Respir J 1995;8:866-68.
29. Lee M, Berger HW. Eosinophilia caused by rifampicin. Chest 1980;77:579.
30. Lange P, Oun H, Fuller S, Turney JH. Eosinophilic colitis due to rifampicin (letter). Lancet 1994;344:1296-7.
31. Lee M, Berger HW. Eosinophilia. Southern Med J 1986;79: 608-12.
32. Kayanakis JG, Giraud P, Fauvel JM, Bounhoure JP. Eosinophilia during captopril treatment (letter). Lancet 1980;2:923.
33. Watanabe K, Nishmura K, Shiode M, Sekiya M, Ikeda S, Inque Y et al. Captopril, an angiotensin-converting enzyme inhibitor, induced pulmonary infiltration with eosinophilia. Int Med 1996;35:142-5.
34. Barnes JN, Davies ES, Gent CB. Rash, eosinophilia and hyperkalaemia associated with enalapril (letter). Lancet 1983;2:41-2.
35. Benard A, Melloni B, Gosselin B, Bonnaud F, Wallaert B. Perindopril-associated pneumonitis. Eur J Respir 1996;9: 1314-16.
36. Wathen CG, MacDonald T, Wise LA, Boyd SM. Eosinophilia associated with spironolactone (letter). Lancet 1986;327: 919-20.
37. Dominguez EA, Hamill RJ. Drug-induced fever due to diltiazem. Arch Intern Med 1991;151:1869-70.
38. Almeyda J, Levantive A. Cutaneous reactions to cardiovascular drugs. Br J Dermatol 1973;88:313-7.
39. Taliercio CP, Olney BA, Lie JT. Myocarditis related to drug hypersensitivity. Mayo Clin Proc 1985;60:463-8.
40. Bacon HM. Eosinophilia associated with chlorpromazine therapy. Am J Psychiatry 1964;120:915-6.
41. Prakash R. In: Keshaven MS, Kennedy JS (editors). Adverse hematological effects in drug-induced dysfunction in psychiatry. New York:Hemisphere Publishing Corporation, 1992.
42. Amsterdam JD. Loeffler’s syndrome: an uncommon adverse reaction to imipramine. Int Clin Psychopharmacol 1986;1: 260-2.
43. Salerno SM, Strong JS, Roth BJ, Sakata V. Eosinophilic pneumonia and respiratory failure associated with a trazodone overdose. Am J Respir Crit Care Med 1995;152:2170-2.
44. Anderson BN, Henrikson IR. Jaundice and eosinophilia associated with amitriptyline. J Clin Psychiatry 1978;39:730-1.
45. Milburn DS, Myers CW. Tryptophan toxicity: a pharmacoepidemiologic review of eosinophilia-myalgia syndrome. DICP Ann Pharmacother 1991;25:1259-62.
46. Current Problems in Pharmacovigilance, 1994. L-tryptophan (Optimax): limited availability for resistant depression. 20:2.
47. Kaufman LD, Gruber BL, Gregerson PK. Clinical follow-up and immunogenic studies of 32 patients with eosinophilia-myalgia syndrome. Lancet 1991;337:1071-4.
48. Swygert LA, Maes EF, Sewell LE, Miller L, Falk H, Kilbourne EM. Eosinophilia-myalgia syndrome: results of national surveillance. JAMA 1990;264:1698-1703.
49. Campbell DS, Morris PD, Silver RM. Eosinophilia-myalgia syndrome: A long-term follow-up study. Southern Med J 1995;88:953-8.
50. Weber RW. Guest editorial: adverse drug effects and the spectrum of eosinophilic pulmonary disorders. Ann Allergy Asthma Immunol 1995;75:451-3.
51. Salzman MB, Valderrama E, Sood SK. Carbamazepine and fatal eosinophilic myocarditis (letter). N Engl J Med 1997; 336:878-9.
52. Mahatma M, Haponik EF, Nelson S, Lopez A, Summer WR. Phenytoin-induced acute respiratory failure with pulmonary eosinophilia. Am J Med 1989;87:93-4.
53. Lazoglu AH, Boglioli LR, Dorsett B, Macris NT. Phenytoin-related immunodeficiency associated with Loeffler’s syndrome. Ann Allergy Asthma Immunol 1995;74:479-82.
54. Kaufman J, O’Shaughnessy IM. Eosinophilic pleural effusion associated with valproic acid administration. Southern Med J 1995;88:881-2.
55. Rich MW, Thomas RA. A case of eosinophilic pneumonia and vasculitis induced by diflunisal. Chest 1997;111:1767-9.
56. Goodwin SD, Glenny RW. Non-steroidal anti-inflammatory drug-associated pulmonary infiltrates with eosinophilia. Arch Intern Med 1992;152:1521-4.
57. Khalid H, Molinary E, Stoller JK. Diclofenac-induced eosinophilic pneumonitis. Ibid 1993;153:1649-52.
58. Quinn JP, Weinstein RA, Caplan LR. Eosinophilic meningitis with ibuprofen therapy. Neurology 1984;34:108-9.
59. Jessop JD, Dippy J, Turnbull A, Bright M. Eosinophilia during gold therapy. Rheumatol Rehab 1974;13:75-9.
60. Edelman J, Davis P, Owen ET. Prevalence of eosinophilia during gold therapy for rheumatoid arthritis. J Rheumatol 1983;10:121-3.
61. Edelman J, Mastaglia GL, Owen ET. The clinical significance of eosinophilia during gold salt therapy in rheumatoid arthritis. Aust N Z J Med 1981;11:723.
62. Cooke N, Bamji A. Gold lung. Rheumatol Rehab 1981;20: 129-35.
63. Martin DM, Goldman JA, Gilliam J, Nasrallah SM. Gold-induced eosinophilic enterocolitis: response to oral cromolyn sodium. Gastroenterology 1981;80:1567-70.
64. Andreu V, Bataller R, Caballeria J, Rodes J. Acute eosinophilic pneumonia associated with ranitidine. J Clin Gastroenterol 1996;23:160-2.
65. Gafter U, Komlos L, Weinstein T, Zevin D, Levi J. Thrombocytopenia, eosinophilia and ranitidine. Ann Intern Med 1987;106:477.
66. Tishler M, Abramov AL. Cimetidine-induced eosinophilia. Drug Intell Clin Pharm 1985;19:377-8.
67. Smith JD, Chang KL, Gums JG, Lugo SI, Parent M. Possible lansoprazole-induced eosinophilic syndrome. Ann Pharmacother 1998, 32:196-200.
68. d’Adamo G, Spinelli C, Forte F, Gangeri F. Omeprazole-induced acute interstitial nephritis (case report). Ren Fail 1997; 19:171-5.
69. Timmer R, Duurkens VAM, Van Hees PAM. Sulphasalazine-induced eosinophilic pneumonia. Neth J Med 1992;41:153-7.
70. Bitton A, Peppercorn MA, Hanrahan JP, Upton MP. Mesalazine-induced lung toxicity. Am J Gastroenterol 1996; 91:1039-40.
71. Bell RJM. Pulmonary infiltration with eosinophils caused by chlorpropamide. Lancet 1964;1:1249-50.
72. Diffee JJ III, Hayes JM, Montesi SA, Greene WL, Milnor P Jr. Chlorpropamide-induced pulmonary infiltration and eosinophilia with multisystem toxicity. J Tenn Med Assoc 1986;79:82-4.
73. Parker PH, Ghishan FK, Shanks D, Greene HL. Eosinophilia associated with cholestyramine. Clin Pediatr Philadelphia 1981;20:675-6.
74. Marcos Sanchez F, Aparicio Martinez JC, Duran Perez-Navarro A. Eosinophilia induced by heparin of low molecular weight. Ann Med Interne 1992;8:256.
75. Pfitzenmeyer P, Meier M, Zuck P, Peiffer G, Masson P, Turcu A et al. Piroxicam induced pulmonary infiltrates and eosinophilia. J Rheumatol 1994;21:1573-7.
76. Bando T, Fujimura M, Noda Y, Hirose J-I, Ohta G, Matsuda T. Minocycline-induced pneumonitis with bilateral hilar lymphadenopathy and pleural effusion. Int Med 1994;33: 177-9.
77. Umeki S. Re-evaluation of eosinophilic pneumonia and its diagnostic criteria. Arch Intern Med 1992;152:1913-9.
78. Bain GA, Flower CDR. Pulmonary eosinophilia. Eur J Radiol 1996;23:3-8.