Viruses and Adverse Drug Reactions
Drug-disease interactions can
have serious consequences
Sandra Knowles, B.Sc.Phm.
An adverse drug reaction (ADR) is defined as any noxious, unintended or undesired effect of a drug, which occurs at doses used in humans for prophylaxis, diagnosis or therapy.1 Epidemiological studies have shown that ADRs occur in approximately 10-20 per cent of all hospitalized patients,2 and three to six per cent of all hospital admissions are the result of an ADR.3 The direct hospital cost to treat these ADRs has been estimated at $1.56 billion annually in the U.S.4 Fatal and/or serious ADRs have been estimated to be the fourth leading cause of death in the U.S.5
ADRs can be divided into those that are predictable and those that are unpredictable (see Table 1). Predictable reactions account for at least 80 per cent of all ADRs, are produced by the pharmacological action of the drug and are dose-related. Examples include overdosage and side effects. In contrast, unpredictable reactions are uncommon and are not dose-dependent. Allergic drug reactions, pseudoallergic drug reactions and idiosyncratic drug reactions are unpredictable drug reactions.6
In this classification scheme, drug-disease interactions resulting in an ADR are considered to be “predictable” reactions. However, although these ADRs can often be pre-dicted, we cannot always predict when and why certain disease conditions will increase the incidence of an ADR. For example, the role that viral infections play in the development of an ADR is, in many instances, still unknown. This article will explore the evidence for viral-drug interactions in the induction of an ADR and will also describe several viral exanthems which may resemble a drug-induced skin eruption.
In 1984, it was hypothesized that underlying viral diseases might increase infected patients’ susceptibility to ADRs by creating biologic alterations in the immune system.7 Examples include ampicillin rash with infectious mononucleosis, the development of Reye’s syndrome resulting from the use of acetylsalicylic acid (ASA), and hypersensitivity reactions to sulfonamides in patients with HIV infections.
Infectious mononucleosis, a primaryinfection caused by the Epstein-Barr virus (EBV), presents as malaise, fever, pharyngitis and lymphadenopathy. Approximately 16 per cent of patients infected with EBV, but who are not on any medication, will develop a rash. Skin rash has been reported to occur in about eight per cent of hospital patients, without concurrent EBV, who are treated with ampicillin. However, almost 100 per cent of patients who are both infected with EBV and treated during the acute phase with ampicillin, will develop an extensive maculopapular pruritic rash within seven to 10 days after initiation of therapy.8,9 In one retrospective study of 184 patients with infectious mononucleosis, 121 had received one or more antibiotics prior to admission, often for treatment of a “sore throat.” Sixteen per cent (10/63) of patients who had not received any antibiotics prior to hospitalization developed a rash. This compared to 29/67 (43 per cent) given penicillin, 2/17 (12 per cent) administered tetracycline and 18/19 (95 per cent) of patients treated with ampicillin.10 Other investigators have found similar results.11 In addition, patients with cytomegalovirus infection, hyperuricemia, chronic lymphocytic leukemia12 and those receiving allopurinol13 are also at increased risk of developing a maculopapular rash when ampicillin is given concurrently.
Researchers found an increased immunologic response, through an increase in immunoglobulin (Ig) M and IgG antibodies, in patients with infectious mononucleosis who received ampicillin.14 Although the etiology of the ampicillin rash is still unknown, it does not appear to be IgE-mediated (i.e., penicillin skin testing is negative in these patients). As such, patients with infectious mononucleosis who have one isolated incident of developing a maculopapular rash after administration of ampicillin are not at risk of a severe allergic reaction upon re-exposure to ampicillin.7
Because of the structural similarity between ampicillin and amoxicillin, it is believed that amoxicillin interacts with EBV as well. As such, it is recommended that clinicians not use ampicillin or amoxicillin therapy for sore throats, especially if the differential diagnosis includes infectious mononucleosis.15
Reye’s syndrome was first described in 1963. It is characterized by an encephalopathic illness combined with fatty degeneration of the liver. Severe vomiting is followed by drowsiness, which may progress to deep coma. There is no jaundice; however, serum transaminase levels and blood ammonia are raised. As well, some patients may develop hypoglycemia and low prothrombin levels.17
Initially, various investigators postulated that this syndrome represented a new viral disease or was associated with specific environmental factors such as pesticides.18 However, in the early 1980s an association was made between dose-related salicylate toxicity and an underlying viral infection.19 During one outbreak of influenza A, all seven patients who developed Reye’s syndrome had taken salicylates, compared to only eight of the sixteen control subjects. Subsequent studies confirmed a strong association between Reye’s syndrome and the ingestion of salicylates (specifically ASA) in children with viral infections, in particular those caused by influenza B and varicella-zoster viruses.20,21 Nevertheless, the interaction between salicylate ingestion and viruses has yet to be elucidated.
In 1982, the U.S. Food and Drug Administration issued a warning regarding the use of ASA in children and adolescents with a feverish illness. The diminished use of ASA was associated with a decrease in the incidence of Reye’s syndrome.22 Although ASA is no longer recommended for the treatment of a fever in North America, some other countries still advocate the use of ASA in children. Parents who travel abroad should be warned regarding this potential risk.23
Hypersensitivity reactions to sulfonamides
in patients with HIV infections
ADRs to trimethoprim-sulfamethoxazole (TMP-SMX) in HIV-infected patients are similar to those reported in non-HIV-infected patients. However, the frequency is greater in the HIV-infected population.25-29 Common toxicities in all patients include dermatologic reactions, hepatitis, hematologic abnormalities, hyponatremia, hyperkalemia, gastrointestinal effects (e.g., nausea and vomiting) and fever.24
In clinical trials using TMP-SMX as a treatment for Pneumocystis carinii pneumonia (PCP) in HIV patients, between 24 to 57 per cent of patients had to discontinue the agent because of ADRs.25,26 When minor reactions were included in the analysis, nearly 100 per cent of patients experienced an ADR following treatment with TMP-SMX.27 In a retrospective study comparing AIDS patients with other immunosuppressed patients with PCP, the prevalence of ADRs with TMP-SMX was 65 per cent and 12 per cent, respectively.28 ADRs to TMP-SMX (including those not requiring discontinuation of the agent) have been reported in 31 per cent and 52 per cent of HIV-infected patients receiving primary or secondary prophylaxis.29 Therefore, the incidence of ADRs is substantially higher in patients receiving TMP-SMX for treatment than in those receiving TMP-SMX for prophylaxis.
The underlying mechanism for the development of TMP-SMX-related ADRs is unclear. Because AIDS patients exhibit a large variety of ADRs, several mechanisms may be involved, including cytokine- and IgE-mediated reactions,30 formation of toxic metabolites31 and viral infection.37
The role of viral infection in stimulating cutaneous reactions in general is poorly understood. The maculopapular rash that develops in HIV-infected patients given TMP-SMX is strikingly similar to the ampicillin-induced rash observed inpatients with EBV. Because EBV infection is common in HIV-infected patients, it is not known whether the increased incidence of rash is due to HIV or reactivated EBV infection.32
An increased risk of ADRs in patients with HIV infection has also been noted for several other drugs including dapsone, carbamazepine and penicillins.33 Although the mechanism responsible for TMP-SMX- and other drug-induced cutaneous reactions in HIV-infected patients is unknown, some authors suggest that defects in both T and B cells may induce multiple drug allergies in susceptible HIV-infected patients.34 For example, a 37-year-old patient with AIDs who had previously tolerated multiple courses of penicillins and sulfonamides developed either an urticarial or a maculopapular rash in response to sulfasalazine, ampicillin, sodium diatrizoate-meglumine diatrizoate and carbamazepine. All reactions resolved after discontinuation of the medication.34
Other examples of potential viral-drug interactions resulting in an ADR include:
- the dose of acetaminophen that is necessary to induce centrilobular necrosis in the liver has been shown to be substantially lower in mice infected with influenza B virus35 and in humans with infectious mononucleosis 36
- patients with AIDS who developed Kaposi’s sarcoma had a higher rate of inhaled nitrite use (for sexual pleasure) than those who did not develop Kaposi’s sarcoma37
- ASA-induced asthma in patients with viral respiratory infections.37 It has been postulated that specific cytotoxic lymphocytes are produced in response to viral infection of the respiratory tract. Prostaglandin E2 inhibits their activity. However, ASA and NSAIDs which inhibit cyclo-oxygenase permit these lymphocytes to attack virally infected target cells. This results in a cascade effect producing asthma-like symptoms.
- in one study, four per cent of 319 patients with drug-induced agranulocytosis, compared with 0.5 per cent of the controls, had a long-term history of infectious mononucleosis37
INDUCED BY VIRAL INFECTIONS
By depressing the metabolizing capacity of the liver, viruses can produce interactions with drugs. As a result of this compromised drug metabolism, serious ADRs can occur in virus-infected patients. The cytochrome P-450 enzyme system, which is responsible for the biotransformation of many drugs, has been shown to be depressed during the course of certain viral infections in animals and humans. It has been postulated that virus-induced interferon production leads to cytochrome P-450 inhibition.37
Theophylline and influenza
There have been several reports of an increase in the half-life of theophylline in children during the presence of a viral upper respiratory tract infection.38,39 During an influenza A and parainfluenza virus outbreak, a significant rise occurred in the percentage of routine samples submitted to a laboratory for analysis for theophylline serum concentration.38 During an influenza epidemic in 1980, 11 children were admitted with high theophylline levels. These children had no history of elevated levels, and all levels returned to normal following the viral infection.39
in HIV-positive patients
Sulfamethoxazole (SMX) is metabolized by the enzyme N-acetyltransferase and the cytochrome P-450 system. A hydroxylamine derivative is produced that can undergo further oxidation to form nitroso metabolites49. Both thehydroxylamine and nitroso metabolites of sulfonamides are toxic in various in vitro systems and can lead to the development of hepatitis, toxic epidermal necrolysis |and other serious side effects (e.g., hematologic toxicities).40 Trimethoprim can also be metabolized to hydroxylamine intermediates.
The rate of formation of the reactive hydroxylamine metabolite is determined by the acetylator status of the individual.41 In patients who are slow acetylators, a larger percentage of SMX is available for metabolism by an alternative pathway that results in toxic by-products, predisposing these patients to more ADRs. For example, in 21 healthy individuals with prior idiosyncratic reactions to sulfonamides, 19 (90 per cent) were slow acetylators.42
Similarly, HIV-infected patients with a history of TMP-SMX idiosyncratic reactions are more likely to express the slow-acetylator phenotype. In one study, 15 of 16 HIV-infected subjects (94 per cent) with a previous hypersensitivity to TMP-SMX (defined as cutaneous morbilliform eruption, fever and hepatic or renal dysfunction) expressed the slow-acetylator phenotype, compared with only five of 12 (42 per cent) without prior hypersensitivity reactions.43 In addition, a slow-acetylator phenotype was more common in patients with advanced HIV infection than in healthy controls. Another study showed that AIDS patients with acute illnesses had an increased prevalence of slow acetylation of TMP-SMX.44
The hydroxylamine metabolite is inactivated primarily by glutathione. In HIV-infected patients, glutathione concentrations in both serum and bronchoalveolar lavage fluid are significantly reduced.45 Because glutathione plays a major role in hydroxylamine metabolite inactivation, a glutathione deficiency in HIV-positive individuals may lead to a reduction in the ability of these patients to scavenge reaction metabolites produced by SMX.31
Therefore, the increase in ADRs associated with TMP-SMX in HIV-infected patients may be due to increased production of a reactive metabolite combined with the patient’s relative inability to detoxify this metabolite.
Viral infections can induce acute, generalized cutaneous eruptions in susceptible individuals. Unfortunately, many of these viral exanthems are difficult to differentiate from bacterial and rickettsial infections, as well as drug eruptions (see Table 2). In addition, because antibiotics are often inappropriately prescribed for viral infections, it is almost impossible to make a causality assessment of a “rash” occurring seven to 10 days after initiation of the antibiotic. In many cases, the antibiotic is automatically assumed to be the culprit without any consideration given to viral exanthems.
Although a comprehensive discussion of viral exanthems is beyond the scope of this article, this next section highlights some of the more common viral exanthems (see Table 3) to assist pharmacists ascertain whether the eruption is in fact drug-induced, or is a result of the viral infection.
Erythema infectiosum, also known as fifth disease, is a childhood disease caused by parvovirus B19. The exanthem is most common in school-aged children, and is spread through respiratory secretions. The incubation period is between four and 14 days. Most children present with a low-grade fever, malaise and headache for one to two days before skin lesions appear. First, a fiery red, macular erythema appears on the cheeks (resembling slapped cheeks), followed by discrete erythematous macules and papules which may evolve into a characteristic lacy pattern. During the next few weeks, the exanthem may improve or worsen depending on changes in environmental temperature, exposure to sunlight, exercise, crying and emotional factors.47,48
Roseola, a common illness in children aged six months to three years, is characterized by a high fever of three to five days’ duration, followed by a maculopapular rash. The exanthem usually fades within hours or days after its first appearance.46,47 Human herpes virus 6 (HHV-6) has been identified as the etiologic agent.46 The mode of transmission is not known, although it is believed to be from asymptomatic adults through salivary shedding. After the initial infection, the virus may persist in a latent phase. Although in most children roseola is a self-limited disease, HHV-6 has been implicated in other diseases such as pneumonitis. As well, neurologic complications can include febrile seizures and rarely encephalitis.
Enteroviruses can cause a variety of exanthems including morbilliform, macular, papular and urticarial lesions.46 The hand-foot-and-mouth syndrome is characterized by the development of a fever followed by vesicles appearing on the buccal mucous membranes, and the hands and feet. Without treatment the exanthem usually resolves within days.
THE PHARMACIST’S ROLE
When a patient develops an ADR, the pharmacist is often asked to determine whether any of the drugs the patient was taking could have contributed to the development of the ADR. Obviously this is a monumental task in most situations, especially if the patient is on multiple medications. Pharmacists play an important role in educating other health professionals about the risk of using certain drugs in specific patient populations because of the increased potential for ADRs in these situations. Obviously, the most important approach to decreasing ADRs, especially for antibiotic-related effects, is the judicious use of drugs.
Sandra Knowles is a pharmacist in the Glaxo-Wellcome-Sunnybrook Drug Safety Clinic at Sunnybrook and WHealth Sciences Centre, North York, On.
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|TABLE 1: CLASSIFICATION OF ADVERSE DRUG REACTIONS|
(also known as Type A)
(also known as Type B)
|1. Overdosage/toxicity: e.g., nephrotoxicity caused by elevated aminoglycoside levels2. Side effects: e.g., constipation caused by chronic opiate use
3. Secondary or indirect effects
4. Drug interactions: e.g., use of terfenadine in combination with ketoconazole can result in torsades de pointes caused by elevated terfenadine levels
|1. Intolerance: e.g., tinnitus caused by small doses of ASA2. Allergic (hypersensitivity or immunologic): result of an immune response to a drug, e.g., penicillin-induced urticaria
3. Pseudoallergic (non-immunologic): immediate, generalized reaction involv-ing mast cell mediator release, e.g., respiratory symptoms induced by ASA and other nonsteroidal anti-inflammatory drugs
4. Idiosyncratic: unexpected response to a drug and differing from its pharmacological actions; not related to an allergic mechanism, e.g., anticonvulsant hypersensitivity syndrome reaction (characterized by fever, cutaneous eruption and internal organ involvement)
|TABLE 2: DIFFERENCES BETWEEN VIRAL EXANTHEMS AND DRUG ERUPTIONS|
|Viral exanthem||Drug eruption|
(e.g., fever, lymphadenopathy)
|Yes||Usually absent (unless drug eruption is part of a generalized drug eruption such as the anticonvulsant hypersensitivity syndrome reaction)|
|Recurrences||No||Yes–if re-exposed to drug|
|Concurrent illness in friends/family||Yes, often||No|
(e.g., age of patient, season)
|TABLE 3: VIRAL EXANTHEMS WHICH MAY MIMIC DRUG ERUPTIONS|
|Disease||Usual season||Usual age||Prodromal symptoms||Description|
|Erythema infectiosum||Winter/spring||5-15 years||Usually none||Slapped cheek appearance initially, followed by “lace-like” rash|
|Roseola||Spring/fall||6 months-3 years||High fever for||Maculopapular rash after defervescence|
|Enteroviral exanthems||Summer/fall||Young children||Occasional fever||Can present as maculopapular, urticarial, vesicular|
|Epstein-Barr exanthems||Any season||Young children/adolescen||Fever, sore throat, adenopathy||Maculopapular ormorbilliform|