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Journal of Clinical Immunology, Vol. 11, No. 2, 1991 Special Article Allergic Manifestations of Human Immunodeficiency (HIV) Infection ANDREW CARR, 1 DAVID A. COOPER, 1'2 and RONALD PENNY 1 Virus Accepted: November I5, 1990 Drug allergy is the most common and significant allergic manifestation of HIV 3 infection. Initially described in patients treated with SMX-TMP for PCP, allergy is now known to involve a multitude of drugs. The pathogenesis of, and risk factors for, allergy in HIV infection are poorly understood, although there is evidence suggesting that allergy is more common with advancing immunode- ficiency. HIV-negative subjects with sulfonamide allergy may have drug-specific antibodies and drug metabotite- induced lymphocyte cytotoxicity, abnormalities that could partly explain the allergic mechanisms and which may have future diagnostic potential; these abnormalities have not been described in HIV-infected subjects. Ther- apy includes avoidance, suppressive agents such as cor- ticosteroids, and desensitization, although the appropri- ate role for each is not entirely clear. Serum IgE levels have been shown to rise with progressive disease; those patients with higher levels may have a worse prognosis. The mechanisms of this rise are multifactorial, probably a combination of altered T-lymphocyte regulation of IgE synthesis and of production of specific IgE directed against microbial antigens. KEY WORDS: Drug hypersensitivity; human immunodeficiency virus (HIV); IgE; desensitization; Pneumocystis carinii pneumo- nia. 1Centre for Immunology, St. Vincent's Hospital, Darlinghurst, Sydney, Australia 2010. ZNational Centre of HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia. 3Abbreviations used: HtV, human immunodeficiency virus: SMX-TMP, sulfamethoxazole-tlimethoprim: PCP, Pneumocys- tis carinii pneumonia; IgE, Immunoglobutin E; EBV, Epstein- Barr virus; CMV, cytomegalovirus; IFN, interferon; IL, inter- leukin. INTRODUCTION Study of allergic disease in HIV 3 infection has focused on two areas, namely, drug allergy and regulation of IgE synthesis by T lymphocytes. Drug allergy was the first clinical manifestation of allergy described in HIV infection and remains the most important. HIV-infected patients treated with high- dose SMX-TMP for PCP were found to develop cutaneous reactions at a greater frequency than either immunocompetent or HIV-negative immuno- deficient subjects (I, 2). These reactions are pre- sumed to have an allergic (i.e., immune-mediated) basis. The clinical features and frequency of drug allergy have been described, and drug allergy has since been identified in HIV-infected patients with the use of multiple drugs. The occurrence of drug hypersensitivity appears paradoxical, considering the profound anergy that develops in these patients to other immune stimuli; this paradox has yet to be explained. An improved understanding of both the underlying risk factors and mechanisms, neither of which have been studied to any significant degree, will allow for improved strategies to circumvent this hypersensitivity. One therapeutic strategy has been desensitization, which has allowed for improved therapy for some allergic patients. Abnormalities of IgE synthesis have been de- scribed in immunodeficiency states of T lympho- cytes other than HIV infection, both congenital and acquired, such as the Wiskott-Aldrich syndrome and acute graft-versus-host disease. In HIV infec- tion, a progressive rise in serum IgE levels has been found and attributed to alterations in the levels of T 55 0271-9142/91/0300-0055506.50/0 © 1991 Plenum Publishing Corporation

Allergic manifestations of human immunodeficiency virus (HIV) infection

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Journal of Clinical Immunology, Vol. 11, No. 2, 1991

Special Article

Allergic Manifestations of Human Immunodeficiency (HIV) Infection

ANDREW CARR, 1 DAVID A. COOPER, 1'2 and RONALD PENNY 1

Virus

Accepted: November I5, 1990

Drug allergy is the most common and significant allergic manifestation of HIV 3 infection. Initially described in patients treated with SMX-TMP for PCP, allergy is now known to involve a multitude of drugs. The pathogenesis of, and risk factors for, allergy in HIV infection are poorly understood, although there is evidence suggesting that allergy is more common with advancing immunode- ficiency. HIV-negative subjects with sulfonamide allergy may have drug-specific antibodies and drug metabotite- induced lymphocyte cytotoxicity, abnormalities that could partly explain the allergic mechanisms and which may have future diagnostic potential; these abnormalities have not been described in HIV-infected subjects. Ther- apy includes avoidance, suppressive agents such as cor- ticosteroids, and desensitization, although the appropri- ate role for each is not entirely clear. Serum IgE levels have been shown to rise with progressive disease; those patients with higher levels may have a worse prognosis. The mechanisms of this rise are multifactorial, probably a combination of altered T-lymphocyte regulation of IgE synthesis and of production of specific IgE directed against microbial antigens.

KEY WORDS: Drug hypersensitivity; human immunodeficiency virus (HIV); IgE; desensitization; Pneumocystis carinii pneumo- nia.

1Centre for Immunology, St. Vincent's Hospital, Darlinghurst, Sydney, Australia 2010.

ZNational Centre of HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia.

3Abbreviations used: HtV, human immunodeficiency virus: SMX-TMP, sulfamethoxazole-tlimethoprim: PCP, Pneumocys- tis carinii pneumonia; IgE, Immunoglobutin E; EBV, Epstein- Barr virus; CMV, cytomegalovirus; IFN, interferon; IL, inter- leukin.

INTRODUCTION

Study of allergic disease in HIV 3 infection has focused on two areas, namely, drug allergy and regulation of IgE synthesis by T lymphocytes. Drug allergy was the first clinical manifestation of allergy described in HIV infection and remains the most important. HIV-infected patients treated with high- dose SMX-TMP for PCP were found to develop cutaneous reactions at a greater frequency than either immunocompetent or HIV-negative immuno- deficient subjects (I, 2). These reactions are pre- sumed to have an allergic (i.e., immune-mediated) basis. The clinical features and frequency of drug allergy have been described, and drug allergy has since been identified in HIV-infected patients with the use of multiple drugs. The occurrence of drug hypersensitivity appears paradoxical, considering the profound anergy that develops in these patients to other immune stimuli; this paradox has yet to be explained. An improved understanding of both the underlying risk factors and mechanisms, neither of which have been studied to any significant degree, will allow for improved strategies to circumvent this hypersensitivity. One therapeutic strategy has been desensitization, which has allowed for improved therapy for some allergic patients.

Abnormalities of IgE synthesis have been de- scribed in immunodeficiency states of T lympho- cytes other than HIV infection, both congenital and acquired, such as the Wiskott-Aldrich syndrome and acute graft-versus-host disease. In HIV infec- tion, a progressive rise in serum IgE levels has been found and attributed to alterations in the levels of T

55 0271-9142/91/0300-0055506.50/0 © 1991 Plenum Publishing Corporation

56 CARR, COOPER, AND PENNY

lymphocyte-derived cytokines and, also, to specific microbial antigens. Specific IgE may have clinical significance; Pneumocystis carinii-specific IgE has been proposed as a possible contributing factor in the acute pneumonitis, seen early in the treatment of PCP, that can be suppressed with corticoster- oids. The rise in total serum IgE has also been shown to have prognostic value in some patients and should prove of clinical value if found to be independent of other prognostic markers.

FREQUENCY OF DRUG ALLERGY

Sulfonamides

Before the advent of HIV, SMX-TMP had been shown to be the therapy of choice for PCP, as it caused less toxicity than pentamidine and was more effective (3, 4). However, in HIV-infected patients with PCP, toxicity with the use of SMX-TMP occurred in 65% of patients, compared to just 12% of HIV-negative immunosuppressed patients (5).

More specifically, the frequency of SMX-TMP allergy differs markedly among subjects who are immunocompetent, HIV-infected, or immunodefi- cient but HIV-negative. In the largest study of SMX-TMP allergy in the general population, 38 cutaneous reactions were found in 1121 patients (3.3%) who received SMX-TMP; 19 of these reac- tions occurred within 3 days, and the remainder within 2 weeks (6). This patient cohort was based upon admissions to several general medical, surgi- cal, and psychiatric wards unlikely to contain immunosuppressed patients and, as such, corre- sponds best with the general community. Similarly, of 19 H/V-negative immunosuppressed adults with PCP treated with SMX-TMP, only I patient devel- oped a drug rash (7, 8). However, the frequency of SMX-TMP allergy in HIV-positive patients has been estimated at between 29 and 65% (5, 9-11) (Table I).

However, only 0-33% of those in the above studies needed to discontinue therapy as a result of hypersensitivity. This wide variation was partially dependent upon the severity both of the reaction and of the PCP itself. In those patients in whom allergy was associated with high fever, Stevens- Johnson syndrome, or presumed visceral involve- ment, therapy was usually ceased (9). In contrast, patients with milder PCP may have required a shorter course of therapy and, so, would have been

Table I. Frequency of Drug Allergy

• Allergy to sulfonamides complicating treatment and prophylaxis of PCP in 30-65% of patients; prevalence with other drugs unclear

• Allergy more common in HIV-infected than in immunocompetent or HIV-negative immunosuppressed patients

• Allergic manifestations may resolve without ceasing therapy in 30% of cases

• Up to 80% of patients may tolerate sulfonamide for secondary PCP prophylaxis despite allergy during PCP therapy (t4)

• Degree of cross-reactivity between different sulfonamides varies, and may be as low as 10%

• Multiple drug allergies may occur in the one patient

less likely to have had SMX-TMP continued once an allergic reaction had occurred.

Given that 85% of patients will develop PCP at least once (12) and that, futhermore, some 60% of patients will relapse within 1 year of PCP therapy without subsequent prophylaxis (13), both primary and secondary prophylaxis against PCP is now mandatory. Despite the frequency of drug allergy with SMX-TMP, it has the advantages of oral administration, home-based therapy, minimal cost, better protection against extrapulmonary pneumo- cystosis than aerosolised pentamidine, and perhaps a lower overall relapse rate as well.

Hypersensitivity may develop to SMX-TMP ad- ministered as primary or secondary prophylaxis against PCP. SMX-TMP hypersensitivity during secondary prophylaxis following uncomplicated therapy of PCP with SMX-TMP has not been re- ported. Consequently, SMX-TMP may be adminis- tered to these patients without the development of drug allergy. Conversely, not all patients will de- velop hypersensitivity to SMX-TMP given as sec- ondary prophylaxis if they developed hypersensi- tivity to SMX-TMP during therapy of PCP. Fourteen patients who developed fever and rash during SMX-TMP treatment of PCP received sub- sequent oral SMX-TMP as prophylaxis; only three of the paients (21%) developed rashes (14).

The frequency of SMX-TMP hypersensitivity complicating primary prophylaxis was found to be as high as 50%, with a further 30% developing pruritis of uncertain significance (I5). However, only 14% of these subjects needed to discontinue therapy, all of whom developed fever and mucosal inflammation consistent with Stevens-Johnson syn- drome. The different reaction rates in various re- ports are no doubt a reflection of differing dosage regimes and differing criteria for defining drug

Journal of Clinical Immunology, Vol. 11, No. 2, 1991

ALLERGIC MANIFESTATIONS OF HIV INFECTION 57

hypersensitivity, for timing drug withdrawal, and for patient selection.

Therapy of PCP with dapsone caused allergy in 17 to 53% of patients (16-18), although all studies were small. Only 4% of these patients needed to cease therapy because of drug hypersensitivity. However, in the comparative studies of dapsone and SMX-TMP hypersensitivity in PCP patients, there was no differ- ence between the two groups in either the frequency of hypersensitivity or the discontinuation due to hypersensitivity (17, 18). Dapsone has been more widely used as prophylaxis than therapy. The fre- quency of hypersensitivity appears to be less than with SMX-TMP. There is also limited cross-reactivity with SMX-TMP, and it would appear that the major- ity of patients who do react to SMX-TMP can safely tolerate dapsone. However, there are no good data available to confirm these suppositions. The chief caution in the use of dapsone would be for those patients in whom SMX-TMP had induced Stevens- Johnson syndrome or visceral involvement, such as hepatitis or pneumonitis.

Fansidar, a combination of pyrimethamine and sulfadoxine, a long-acting sulfonamide, has been widely used for PCP prophylaxis. The long-acting sulfonamides are no longer used as therapy for com- mon bacterial infections in the general community because of the increased risk of Stevens-Johnson syndrome. The other major use of Fansidar has been as prophylaxis against malaria. However, because of multiple deaths associated with its use, it is likewise no longer recommended by the Centers for Disease Control (19). These deaths have been a result of severe cutaneous exfoliation and sepsis. To date, one fatality has been reported in HIV-infected subjects with its use (20); whether severe reactions are more common than with SMX-TMP or dapsone has not been determined. Moreover, given also that the effi- cacy of Fansidar as prophylaxis appears to be inferior to SMX-TMP or pentamidine, Fansidar is probably best reserved for use as prophylaxis in those in whom they are inappropriate. Two reports of its use in predominantly SMX-TMP allergic subjects found hypersensitivity developed to Fansidar in only I0 and 12% of patients (21, 22), although the nature of their allergic reactions is not always clear from the reports.

Other Drugs

Pentamidine has long been assumed to be a nonallergenic alternative therapy of PCP. However, four reports have documented the occurrence of

morbilliform eruptions presumed secondary to pen- tamidine therapy, including one prospective study with a prevalence of 15% (9). No patient was required to stop pentamidine therapy. One patient developed transient urticaria, without other fea- tures of anaphylaxis, while receiving intravenous pentamidine (23). The urticaria was localized imme- diately proximal to the cannula site and occurred within 5 min of the infusion commencing. Following a single intravenous injection of diphenhydramine, all subsequent infusions were administered without incident. Whether this was type I (i.e., IgE- mediated) hypersensitivity or an anaphylactoid re- sponse is unknown. Similarly, the mechanism re- sponsible for bronchospasm that occurs in a large percentage of patients receiving aerolized pentami- dine is unknown.

Experience with other PCP therapy is less well documented. Rash developed in 9 of 49 patients treated for PCP with trimetrexate, and resolved in all but 1 when concurrent sulfadiazine was ceased. The other patient had ceased all other therapy at least 8 days previously but did not develop a rash with a second course of trimetrexate given several months later (24).

The development of drug hypersensitivity is not limited to the treatment of HIV-infected patients with PCP, also occurring with the use of sulfadiaz- ine (SDZ) as therapy of central nervous system toxoplasmosis (25-27). Reaction rates of 10-40% have been observed, usually resulting in cessation of SDZ and substitution with clindamycin. The latter may also be used as initial therapy in those patients previously allergic to SMX, although clin- damycin is also known to induce drug rashes.

Other antibiotics reported to induce hypersensi- tivity include ampiciUin (28), amoxicillin-clavulanic acid (29), phenytoin (30), carbamazepine (28, 30), isoniazid and other antimycobacterial therapy (31), clindamycin (31), and flucytosine (32). In addition we have also seen reactions to ciprofloxacin, ri- fampicin, fusidic acid, and ganciclovir. Anti-HIV therapy has also been associated with allergic reac- tions, including zidovudine (33, 34). didanosine (ddI) (35), and recombinant soluble CD4 (36). As with sulfonamide hypersensitivity, all reactions were delayed in onset, with the exception of reex- posures. All had clinical manifestations of rash and fever, with the exception of zidovudine. Rechal- lenge of three patients with zidovudine resulted in fever without rash on at least two occasions, al- though there was some evidence that this was

Journal o f Clinical Immunology, Vol. 11, No. 2, 1991

58 CARR, COOPER, AND PENNY

infectious, and not allergic, in nature (33). In an- other patient, however, rechallenge with zidovu- dine was associated with the rapid onset of fever and biopsy-proven leukocytoclastic vasculitis (34).

Multiple drug allergies may develop in the one patient. A patient developed rash and fever on challenge testing to penicillin, clindamycin, trimeth- oprim, erythromycin, rifampicin, isoniazid, pyrazi- namide, ethambutol, prothionamide, streptomycin, and clofazimine (31). Management problems arise when allergy develops to several drugs used for the treatment of one condition, such as to sulfadiazine and clindamycin for the treatment of toxoplasmo- sis. In such instances, there may be no effective alternative, and desensitization may be indicated.

Clinical Features

Hypersensitivity reactions in HIV-infected pa- tients show a high degree of uniformity, despite the multiplicity of causative drugs. The reaction usually begins gradually after 7-12 days of therapy with fever and a morbilliform eruption. Patients with prior exposure may, however, develop immediate, and often severe, reactions. The rash typically consists of erythematous, maculopapular, pruritic, and confluent lesions, most prominent on the body and upper limbs and rarely involving the head. The fever may be accompanied by rigors and be difficult to distinguish from those due to infections; for example, in patients with PCP, superimposed bac- terial bronchopneumonia or mycobacteriosis may also cause fevers. Distinguishing allergy from infec- tion is especially difficult if the fever occurs without an accompanying rash; in particular, mycobacteri- osis, lymphoma, Kaposi's sarcoma, and HIV itself may all cause fever without other clinical manifes- tations. Although the frequency of isolated fever due to drug allergy has not been reported, this appears to be less frequent than combined rash and fever. Other features of hypersensitivity reported in HIV-positive patients include anicteric hepatitis, pneumonitis, and the Stevens-Johnson syndrome (37, 38). There have been no reports, however, of true anaphylaxis (i.e., IgE-mediated allergy) in pa- tients with HIV infection. Whether the hematolog- ical cytopenias associated with drug therapy are due in part to hypersensitivity as well as to bone marrow toxicity is not known. The more recent observation that Pneumocystis carinii may infect extrapulmonary sites suggests that some of these

Table II. Clinical Features of Drug Allergy

• Cardinal features Morbiltiform eruption Fever

• Other features Stevens-Johnson syndrome Hepatitis Acute interstitial pneumonitis

? Hematological toxicity • Occurs after 7-12 days of therapy and may worsen despite

cessation

allergic features may be related to disease rather than to treatment (Table II).

The clinical features of hypersensitivity compli- cating PCP prophylaxis are essentially those de- scribed above, namely, progressive onset of rash and fever, although they need not both occur or commence concurrently. In our experience, rash and fever may take as long as 4 weeks to develop. In some patients treated at our institution with intermittent SMX-TMP (cotrimoxazole DS, one tablet bd twice weekly), the rash may wax and wane following each day's doses. In other patients, how- ever, rash may occur immediately following the first dose, implying prior exposure and sensitization and, perhaps, an IgE-mediated mechanism.

Therapy

Cessation of the drug responsible for an allergic reaction is usually sufficient to ensure resolution of the reaction (Table III). This is not always neces- sary as, for reasons that are unclear, the rash may recede in up to one-third of patients despite contin- ued therapy (9). However, the intensity of drug hypersensitivity may increase for up to 7 days after the offending drug has been ceased and persist for several weeks. For persistent or severe reactions, corticosteroids and antihistamines have been used, although neither has been shown actually to accel- erate the resolution of drug reactions (15, 23). The use of corticosteroids, in particular, must be weighed against their ability to reactivate latent infections, such as cytomegalovirus (CMV) and mycobacteria. Corticosteroids are now being used

Table IlL Therapy of Drug Allergy

• Cessation of drug usually adequate • Therapy of hypersensitivity with corticosteroids and/or

antihistamines not of proven benefit • Desensitization of benefit to patients requiring therapy for

cerebral toxoplasmosis or PCP

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ALLERGIC MANIFESTATIONS OF HIV INFECTION 59

therapeutically for PCP, where they are thought to reduce the inflammatory component (38); this use could reduce the future incidence of hypersensitiv- ity reactions to SMX-TMP.

Desensitization may be appropriate if there is no suitable alternative therapy to an allergenic drug. Early case reports demonstrated successful desen- sitization to SMX-TMP (14, 40, 41) and sulfadiazine (SDZ) (42) of patients with PCP and cerebral toxo- plasmosis, respectively. This was especially of ben- efit for those with cerebral toxoplasmosis, as indef- inite maintenance therapy is required at relatively high dose, SDZ-pyrimethamine has been regarded by many as the more effective therapy, and patients may also be allergic to the other mainstay of treat- ment, clindamycin.

Since 1987, as has been reported (43), some 27 patients have been desensitized on 33 occasions to SDZ at our institution to enable therapy for pre- sumed cerebral toxoplasmosis. This was especially essential for the five patients who had also devel- oped rashes to clindamycin. This protocol has the advantages of oral administration and a lack of dependence upon corticosteroids (42) or antihista- mines to suppress allergy. Of the 27 patients to undergo SDZ desensitisation, a final daily dose of 4 g was achieved in 15 patients and of 2 g in a further 6 patients. Desensitization failed in eight patients, secondary to allergy in five and patient noncompli- ance in three. All of these noncompliant patients were subsequently successfully desensitized.

No conclusive reports of desensitization to other agents have been reported. Other situations in which desensitization may be of use are to B-lactam antibiotics, antituberculous, anticonvulsant, and even anti-HIV therapy.

The mechanisms of successful desensitization are unknown; knowledge in this area could help predict those patients in whom desensitization would be successful.

Mechanisms

There are minimal data regarding risk factors for drug allergy in HIV disease (Table IV). By under- standing such factors, and associated mechanisms, it might be possible to identify those at high risk for developing hypersensitivity and modify their treat- ment accordingly.

The similarity to the ampicitlin-associated rash of acute Epstein-Barr virus (EBV) (44) and acute CMV (45) infections is striking. Subclinical infec-

Table IV. Mechanisms and Risk Factors in Drug Allergy

• Mechanisms unknown No data regarding IgE or immune complex involvement ? Molecular structure of drug and/or metabolite(s)

(? via hepatic cytochrome P450) • Risk factors uncertain

Degree of immunodeficiency- (CD4+ celt count, <200 x t06/1)

Duration and dose of therapy Coexisting viral infection Slow acetylator phenotype Atopic diathesis

tion with these or other agents, such as hepatitis B, or HIV itself, could be involved, given the high prevalence of exposure to these viruses in HIV- infected patients and the ability of EBV, CMV, and HIV to stimulate the immune system. However, allergic reactions to ampicillin are also more com- mon in patients with chronic lymphocytic leu- kaemia (46) and in those receiving allopurinol for the treatment of gout (47), who have no evidence of acute EBV or CMV infection.

Altered immunity per se is another likely expla- nation. Amoxicillin-induced rashes were found in 16 of 25 HIV-positive subjects with CD4+ cell counts less than 200, compared with only 1 of 9 patients with CD4 + cell counts greater than 200 × 106/1 (29). This has not been demonstrated in sulfo- namide-allergic subjects. Given the low molecular weight of SMX and other drugs, a possible cell- mediated hypersensitivity could occur via hapten formation. However, in the case of SMX, there is no specific serum carrier molecule, and binding to albumin is weak and noncovalent.

There are no reports investigating a role of im- mune complex deposition in the pathogenesis of drug allergy in HIV infection, although the delayed nature of the reactions would be more in keeping with such a mechanism rather than an IgE-mediated process.

Given the large number of drugs that can induce rashes in HIV-infected persons, it is unlikely that development of allergy is related solely to their molecular structures, at least in an unbound or unmetabolized form. However, it would seem that reactions to sulfonamide drugs are more common than to other classes of drug, and perhaps a com- mon structural determinant and/or metabolite is involved in the development of sulfonamide hyper- sensitivity.

Six subjects, of unknown HIV status and with sulfadiazine allergy, were all found to express the

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60 CARR, COOPER, AND PENNY

slow acetylator phenotype, compared to a prevalence of 55% in the north American population (48). Con- versely, no increase in the prevalence of this pheno- type was found in a group of HIV-infected patients with either dapsone or SMX-TMP allergy (17).

The development of hypersensitivity could also be dependent upon the dose of drug administered, as PCP is treated with much higher doses of SMX- TMP than infections in the general community. This dose dependence could account for the tolerance of SMX-TMP at a prophylactic dose, despite allergy to the high dose used for PCP (14, 49). Similarly, some patients desensitized to SDZ were able to tolerate a final dose of 2 g per day, having developed a rash at 4 g per day (43). A possible explanation would be the presence of a rate-limiting metabolic pathway of an allergenic metabolite of SMX and SDZ, although this has not been described. Similarly, the increased prev- alence of drug allergy may be dependent upon the longer duration of therapy. The minimum recom- mended period of therapy for PCP is 14 days, whereas common bacterial infections in the general commu- nity tend to be treated with 5 to 7 days of antibiotic.

Whether allergy to a given drug predisposes a patient to develop other drug allergies is not known. Likewise, the role of atopy in the development of drug hypersensitivity is yet to be clarified.

Diagnosis

There is no report of any laboratory investiga- tions to diagnose sulfonamide or other drug allergy in HIV-infected patients. The alternative is drug challenge which may be hazardous and impractical. Arnold et al. (37) reported an individual who had recently developed fever, rash, neutropenia, and abnormal liver function tests during SMX-TMP therapy for PCP. Within 2 hr of the second dose of prophylactic SMX-TMP, the patient developed hypotension, erythroderma, rhabdomyolysis, and acute respiratory failure with pulmonary infiltrates. Fortunately, ventilation was not required and the illness resolved over 48 hr. An additional difficulty of drug challenge presents itself in those patients in whom the diagnosis of drug allergy is based solely upon the development of fever (14, 33). Proof of hypersensitivity may be impossible to obtain, even following challenge, as HIV-infected patients may develop fever, without other clinical manifesta- tions, from a variety of causes.

Intradermal challenge with SMX-TMP was per- formed in a patient with active SMX-TMP allergy

(50), using incremental concentrations. All chal- lenges were negative, although the maximal con- centration used was not stated. This implies that the reactions were not IgE-mediated, although intrader- mal challenge can be negative in those with active allergic reactions and become positive later.

Several avenues of in vitro diagnosis remain to be explored. Rieder et al. (51) examined 31 subjects with SMX-TMP-induced rashes. Their HIV status was not stated, although the subjects were referred from the community to an allergy outpatient service. Like those occurring in HIV-infected patients, their reac- tions clinically were not IgE-mediated, occurring at a mean of 8.3 days therapy, and were a combination of maculopapular rash, toxic epidermal necrolysis, and erythema multiforme, rather than urticaria. An in- crease was found in the cytotoxicity of SMX hydrox- ylamine metabolites (SMX-HA) to mononuclear cells from the SMX-allergic subjects when compared to those of nonallergic subjects. This could not be in- duced by SMX alone and was markedly attenuated by N-acetyl cysteine and glutathione, suggesting a role for hepatic cytochrome P450 in the development of an allergic metabolite. Similar abnormalities were de- tected in a group exposed to SDZ-HA (52). The significance of this cytotoxicity is not known. Sub- jects were not able to be tested prior to their reactions and so it is unknown whether this is a primary or secondary phenomenon. Some subjects exhibited this cytotoxicity up to 2 years after their reactions, sug- gesting a role for this assay as a diagnostic test in those with previous suspected nonanaphylactic reac- tions to SMX or SDZ.

Drug-specific antibodies have not been reported in HIV-infected patients with drug reactions. Harle and Baldo reported the detection of IgE specific for both SMX (53) and TMP (54) in HIV-negative individuals with anaphylactic responses and positive skin-prick testing to SMX-TMP. No patient was allergic to both SMX and TMP. Although it is commonly assumed that all allergy to SMX-TMP in HIV-infected subjects is on the basis of allergy to SMX, this has not been proven, and the degree to which TMP is involved deserves investigation.

IgE AND ATOPY

Recently, data have shown serum IgE levels to be altered in HIV-infected patients with AIDS or AIDS-related complex (ARC). Three studies have found an increase in serum IgE with declining CD4+ cell counts (55-57), and one a decrease (58),

Journal of Clinical Immunology, Vot. 1t, No. 2, 1991

ALLERGIC MANIFESTATIONS OF HIV INFECTION 61

Table V. IgE and HIV Infection

. Increase in serum IgE levels with progressive disease • Causes uncertain

Specific IgE to HIV., microbial antigens including Pneumocystis carinii

Generalized immune dysregulation due to altered production of tL-4 and IFN-~/

• Elevated serum IgE of prognostic significance in late-stage disease

- Prevalence and severity of atopic disease unclear

although all but one were cross-sectional studies. There could be a number of mechanisms to explain these changes. HIV could stimulate production of its own specific IgE. HIV antigen was found to stimulate the basophils of HIV-infected patients, but not of seronegative controls, to release hista- mine, a phenomenon blocked by the removal of IgE (59). Similar findings were seen in HIV-infected persons in response to Candida albicans and Herpes simplex virus type I (60). A preparation of antigen derived from Pneumocystis carinii caused histamine release from basophils in 8 of 12 patients with PCP, but not in HIV seronegatives, and in only 2 of 12 HIV-infected controls without PCP (61). The clinical significance of a Pneumocystis carinii- specific IgE is not known; it was speculated that it could play a role in the clinical decline often seen early in therapy of PCP, a decline that can be suppressed with corticosteroids. Changes in the prevalence of atopy could also account for changes in lgE, although the natural history of atopy in HIV infection is still unknown (Table V).

Finally, progressive HIV infection could well result in the alteration of overall IgE synthesis. Other immune deficiency states of T lymphocytes have also been associated with elevated levels of serum IgE, such as Wiskott-Aldrich syndrome (62), Di George syndrome (63) Hodgkin's disease (64), and acute graft-versus-host disease (65). Altered IgE synthesis is quite possibly a result of changes in the secretion by T lymphocytes of interferon gamma (IFN-~/) and interleukin4 (IL-4). Numerous investigators have demonstrated the roles of IFN--y and IL-4 as respective negative and positive stimuli to IgE synthesis (66, 67). A study of T-cell clones derived from five HIV-infected subjects found a reduction of IFN-~/-secreting clones and a corre- sponding increase in the proportion of IL-4- secreting clones (68). This contrasted with patients with the hyper-IgE syndrome, who had an in- creased number of clones secreting IL-4. The rea- sons for these alterations are not clear, although it is

tempting to speculate that HIV is capable of selec- tively targeting CD4+ subsets, with inhibition of IFN-~ synthesis. IgE-binding factors derive from T lymphocytes and stimulate the transformation of IgE-bearing B lymphocytes to IgE-secreting plasma cells; their role in IgE synthesis in HIV infection is unknown. Likewise, a role for CD23, the low- affinity IgE receptor found on the surface of T lymphocytes, in the altered IgE production of HIV disease has not been investigated.

More recently, IgE was found to have prognostic value in patients with late-stage HIV infection (57). In a 2-year study of 250 patients, those patients at enrollment with CDC group IV A disease and total serum IgE greater than 150 IU/ml had an 83% probability of developing AIDS, compared to 44% of those with IgE less than 150 IU/ml. The corre- sponding probabilities for those with CD4+ cells counts less than 300 × 106/ml at entry were 100 and 9%, respectively. IgE was not, however, found to have predictive value for those with earlier-stage disease, possibly a reflection of the relatively short duration of the study.

A report documented three cases of HIV-infected, nonatopic patients whose predominant clinical feature was a diffuse dermatitis associated with serum levels of IgE above 2000 IU/ml (70). One patient also suf- fered with staphylococcal infections, and the derma- titis responded to zidovudine. A comparison with the hyper-IgE syndrome was made. Whether this is a truly an acquired form of the usually congenital hy- per-IgE syndrome is unclear.

There is little information regarding changes in the prevalence or severity of atopic disease with progressive HIV infection. A small group of pa- tients in the only clinical study (71) had new, recurrent, or worsening atopic manifestations, with no one manifestation or precipitant of atopy pre- dominating. Two of the patients were treated with IFN--¢; one showed improvement of mild asthma and the other of moderately severe milk-induced angioedema. Both patients exhibited a concomitant rise in their CD4+ cell counts, but with cessation of therapy, their atopy rapidly relapsed and CD4+ counts fell.

One study showed a reduction in the prevalence of atopy, as measured by RAST reactivity (72). However, there was no correlation with either clinical histories or results of skin-prick testing. Changes in RAST reactivity could be a reflection of a true change in clinical prevalence or of altered regulation of allergen-specific IgE synthesis.

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62 CARR, COOPER, AND PENNY

SUMMARY

Allergic phenomena have been identified in nu- merous areas of HIV disease, in particular, drug allergy. Further efforts should be focused upon the identification of risk factors to reduce the risk of drug allergy and to identify the underlying mecha- nisms. Investigation of other immune diseases, such as atopy, and the effect of HIV on them, could offer insights into the immunopathogenesis of HIV disease.

ACKNOWLEDGMENT

A.C. is the recipient of a Commonwealth AIDS Research Scholarship.

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