Serum Sickness Reaction Research Articles

IMMUNE MECHANISMS OF DRUG ALLERGY

The majority of adverse reactions to drugs do not involve specific immunologic sensitization (Table 1). Such nonimmunologic reactions include side effects, toxicity, and other pharmacologic effects, and will not be addressed here. Historically, immunologic drug reactions have been described in the context of the Gell and Coombs system (Table 2). This model continues to be useful clinically in certain situations. Indeed, demonstrating the presence of specific IgE to penicillin in the context of an appropriate clinical history has impressive predictive value. This approach, however, has limited use when applied to other drug reactions. For example, the well-known pseudoallergic reactions to nonsteroidal anti-inflammatory drugs (NSAIDs), radiocontrast media, and opiates all may present clinically with immediate urticaria, angioedema, bronchospasm, gastrointestinal distress, and cardiovascular collapse indistinguishable from IgE-mediated anaphylaxis, yet they do not require sensitization and do not appear to be allergenic as haptens or complete antigens. Clinical serum sickness symptoms that have been generally attributed to the Gell and Coombs Type III (i.e., immune complex) mechanism also may be misleading. For example, cells from patients who have had classic serum sickness reactions (e.g., fever, arthralgia, or erythema multiforme) to the antibiotic cefaclor die in vitro when exposed to a metabolized form of the drug, whereas cells from patients without such a history do not die. 23 In addition, immune complexes associated with cefaclor-induced serum sickness have never been identified. This suggests that the serum sickness may be caused by a cytotoxic effect of the drug on cells rather than by an immunologic reaction to the drug. To improve our ability to address these clinical challenges in the future, we must extend our understanding of the mechanisms involved. By definition, a true hypersensitivity response to a drug requires the development of an immune response to that agent. Such an immune response must be similar to the immune response to any antigen. There are several unique aspects of drugs, however, which make their interaction with the immune system unusual. This article provides an overview of how immune responses develop to antigens and emphasizes the unique features pertinent to the development of drug hypersensitivity. The factors that potentially influence the development of drug allergy are summarized in Table 3. Unfortunately, little is understood regarding the immune response to drugs; thus, much of this overview is speculative. This article emphasizes several unique aspects of the immune response to drugs, and most importantly, their function as incomplete antigens (i.e., haptens), which cannot trigger hypersensitivity reactions until they become covalently linked to an appropriate carrier molecule. 13,25,35 Any theory regarding the mechanism of drug allergy must also explain the phenomenon that in contrast to the atopic diseases—allergic rhinitis, asthma, and atopic dermatitis—drug allergies develop with the same frequency in atopic and nonatopic individuals. 2,46 Although atopy is not a risk factor for the development of drug allergy, surprisingly, there may be a familial predisposition. 4 Any mechanism proposed for the development of hypersensitivity toward haptens must provide a mechanism for this genetic predisposition and the tendency to develop multiple drug sensitivities to what are often completely unrelated compounds.

Cefaclor and Serum Sickness-Like Reaction-Reply

In Reply. —Originally, the serum sickness reaction was described following the administration of horse antiserum. Recently, the serum sickness reaction has been associated with the administration of penicillin, hydralazine, sulfonamides, or thiazide diuretics. This clinical entity results from the formation and deposition of detectable antigen-antibody complexes in blood vessels. Subsequent activation of the immune system and release of vasoactive amines results in clinical disease from 1 to 3 weeks, but usually 7 to 10 days after exposure to the antigen. An urticarial or maculopapular skin rash is the most common sign, occurring 90% of the time. Arthralgias occur in 50% of the cases. Fever, lymphadenopathy, and proteinuria are less frequent. The clinical course is usually benign and resolves quickly after withdrawal of the offending antigen. Epinephrine, antihistamines, and/or steroids may be helpful in more severe cases. 1 From the late 1970s through 1991, Eli Lilly and Co collected and investigated spontaneous reports

Cefaclor and Serum Sickness-Like Reaction

To the Editor. —I disagree with Dr Grammer's1admonition that all β-lactam drugs should be avoided in patients who experience a serum sickness reaction to cefaclor. He offers no firm evidence that these patients ever develop serum sickness from other β-lactam drugs. In fact, he cites an article that demonstrates that it is safe to give other cephalosporins to these patients.2 Over the past 9 years, my 3 partners and I have seen about 10 classic serum sickness reaction to cefaclor. We have not avoided subsequent prescription of β-lactam drugs in these patients. Although their reports are anecdotal, none of these patients has had a subsequent serum sickness reaction to any other β-lactam drug. At the time of a 9-month-old patient's cefaclor serum sickness reaction in February 1991, I had a conversation with Jennifer Stotka, MD, at the Medical Department of Eli Lilly and Co, the manufacturer. I

Pilot study of antithymocyte globulin in systemic sclerosis

Between June 1, 1992 and August 31, 1994 we conducted an open pilot study of antithymocyte globulin (ATGAM; Upjohn, Kalamazoo, MI) in 10 patients with early systemic sclerosis (SSc) to assess whether this agent might prevent the progression of cutaneous and pulmonary involvement in this disease. Adult patients with early SSc (< 3 years) and evidence of progressive skin and pulmonary disease were enrolled. All patients were hospitalized and received a single course of intravenous ATGAM, at a dosage of 10 mg/kg over 4 hours, on 5 consecutive days. Patients were followed up at weeks 1, 2, 3, and 4, and months 2, 4, 6, and 12. Patients were considered to be improved if the Rodnan skin score decreased > or = 25%, to be worse if the skin score increased > or = 25%, and to be not improved if the skin score was within 25% of baseline. For pulmonary involvement, patients were considered to be improved if either the diffusing capacity for carbon monoxide or the forced vital capacity was increased > or = 10%, worse if decreased by > or = 10%, and stable if within 10% of baseline. Most patients tolerated the treatment well, although 1 patient developed an allergic reaction necessitating discontinuation of treatment, 1 developed a serum sickness reaction after completion of therapy, and 1 developed a central venous access-related axillary vein thrombosis. Two patients died of SSc-related complications during the followup period. At 12 months, only 2 patients showed improvement in both skin and pulmonary function measures, whereas 5 patients were worse and 3 were stable. At the dosage administered in this study, ATGAM appears ineffective in improving the skin and pulmonary features of SSc.

Animal models of systemic vasculitis.

Necrotizing leucocytoclastic vasculitis is the histopathological hallmark of the small vessel systemic vasculitides (SV), a group of human diseases commonly associated with anti-neutrophil cytoplasm autoantibodies (ANCA). Necrotizing vasculitis is seen in a number of experimental systems, but none of these provide an ideal animal model for human SV. Vasculitis occurs in serum sickness reactions; in murine models of systemic lupus erythematosus; in association with infection, particularly chronic viral infections; and after treatment with certain drugs or inflammatory mediators. 'Spontaneous' vasculitis has been reported in specific mouse strains, especially with ageing, and in some larger species. The size of vessel involved and the type of inflammatory cells predominating are variable in these experimental situations, and none of these models feature antibodies analogous to ANCA. We have recently reported that Brown Norway rats treated with mercuric chloride (HgCl2) develop necrotizing leucocytoclastic vasculitis, especially in the gut, and also develop antibodies to myeloperoxidase (MPO) which recognize similar determinants on MPO to those bound by a subset of ANCA. Transfer of serum from HgCl2-treated rats to naive animals does not induce tissue injury. Preliminary experiments using pooled immunoglobulin or an anti-CD4 monoclonal antibody did not show useful therapeutic benefit from these treatments. HgCl2-induced vasculitis has weaknesses as an animal model of human SV, but is the only experimental model in which anti-MPO autoantibodies have so far been demonstrated, and therefore may be of particular relevance to ANCA-associated SV.

Serum sickness reactions more common with cefaclor

Serum sickness reactions more common with cefaclor

A Technetium-Labeled Monoclonal Antibody for Imaging Metastatic Melanoma

Twenty patients with histologically proven metastatic melanoma were scanned with a 99mtechnetium (99mTc)-labeled melanoma antibody to determine the detection rate of known malignant lesions and to evaluate the antibody's ability to discover occult metastases. Isotope localization in different organs was as follows: liver 100%, bone 100%, subcutaneous lesions 80%, lymph nodes 54%, and lung 33%. Four unsuspected bone lesions and 16 occult subcutaneous lesions were found. False positive lesions were noted in two instances--one benign thyroid adenoma, and one arthritic bone lesion. One patient developed an atypical serum sickness reaction with a rash and arthralgias that responded rapidly to treatment. The 99mTc antimelanoma antibody is a safe and effective method to detect metastatic melanoma. It has potential use for screening newly diagnosed melanomas that carry an increased risk of recurrence.

362 Sulfonamide (SMX) induced serum sickness (SSX) reactions in AIDS

362 Sulfonamide (SMX) induced serum sickness (SSX) reactions in AIDS

401 Serum sickness reaction to natural yellow jacket (YJ) stings associated with significant elevations in YJ-specific IgG1

401 Serum sickness reaction to natural yellow jacket (YJ) stings associated with significant elevations in YJ-specific IgG1

Acute arthropod envenomation. Incidence, clinical features and management.

Black widow spider (Latrodectus mactans) envenomation is found throughout both the temperate and tropical latitudes, and is one of the leading causes of death from arthropod envenomations worldwide. The venom is highly neurotoxic, affecting the presynaptic motor endplate to allow massive noradrenaline (norepinephrine) and acetylcholine release into synapses causing excessive stimulation and fatigue of the motor end plate and muscle. Clinically, patients develop a bite site lesion and pain, abdominal pain and tenderness, and lower extremity pain and weakness within minutes to hours of envenomation. Symptoms progress over several hours, then subside over 2 to 3 days. The recommended treatment of 'common' envenomation is calcium gluconate 10% intravenously, titrated to relief of symptoms; antivenin, although effective, may cause hypersensitivity and serum sickness reactions, and should be restricted to life-threatening envenomations only. Brown recluse spider (Loxosceles reclusa) envenomations are seen in the Americas and in Europe, and are endemic to the south and central United States. The venom contains at least 8 enzymes, consisting of various lysins (facilitating venom spread) and sphingomyelinase D, which causes cell membrane injury and lysis, thrombosis, local ischaemia, and chemotaxis. Local envenomations begin as pain and itching that progresses to vesiculation with violaceous necrosis and surrounding erythema, and ultimately ulcer formation. Systemic envenomations may be life threatening, and present with fever, constitutional symptoms, petechial eruptions, thrombocytopenia, and haemolysis with haemoglobinuric renal failure. Treatment of local envenomations is conservative (local wound care, cryotherapy, elevation, tetanus prophylaxis, and close follow-up); systemic envenomation requires supportive care and treatment of arising complications, corticosteroids to stabilise red blood cell membranes, and support of renal function. Dapsone 100mg daily has emerged as a promising therapeutic agent in both animal studies and clinical trials. Over 650 species of scorpions are known to cause envenomation (mostly in children under 10 years); they are endemic mostly in arid and tropical areas. Different venoms and clinical presentations are seen across the different species. Most commonly, an inflammatory local reaction occurs with envenomation, which is treated with wound debridement and cleaning, tetanus prophylaxis, and antihistamines. Occasionally the venom is allergenic, and the resultant allergic reaction is treated in a standard fashion.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum sickness and erythema multiforme reactions to cefaclor

Serum sickness and erythema multiforme reactions to cefaclor

Rapid serologic diagnosis of serum sickness from antithymocyte globulin therapy using enzyme immunoassay.

Although the use of antithymocyte globulin/antilymphocyte serum (ATG/ALS) has been shown to be beneficial in treating renal allograft rejection, the incidence and nature of serum sickness reactions following such treatment have received limited attention. In the setting of rejection or infection, the diagnosis of serum sickness is often difficult on clinical grounds, and biopsy may be an undesirable means of obtaining documentation. A sensitive enzyme-linked immunosorbent assay (ELISA) was developed to detect antibodies against ATGAM (Upjohn) and was utilized in 35 patients treated for rejection with ATGAM following clinical unresponsiveness to bolus methylprednisolone therapy. Serum sickness was diagnosed clinically in 7 of these patients (20%) during or immediately following ATGAM therapy. Significant titers of anti-ATGAM antibody were found in these 7 cases, as well as 5 additional cases (14%). Upon retrospective review, the diagnosis of serum sickness was also made in each of these 5 additional cases based upon the immunopathologic detection of horse immunoglobulin deposits in vessels of tissue (lung or kidney) examined. In 2 other cases where serologic testing was negative, there was some clinical suggestion of serum sickness that could not be documented pathologically. ELISA for anti-ATGAM antibodies was negative in testing 46 control patients and pooled normal sera. In one case, retrospective testing of pre-ATGAM therapy serum samples showed significant antihorse antibodies. Despite a negative skin test prior to administration, this patient developed symptoms of serum sickness 15 days after the onset of ATGAM therapy. Extremely high titers of antibody were detected 5 days earlier (10 days posttherapy), and the presence of horse immunoglobulin immune complexes in the kidney was documented following graft loss that occurred within 4 weeks. These findings indicate (1) serologic testing for anti-ATGAM antibodies using a sensitive ELISA method provides a quick, inexpensive, noninvasive means for the presumptive diagnosis of serum sickness in complicated clinical situations, and (2) screening of patient sera prior to administration of ATGAM may be useful in avoiding potential serum sickness reactions.

Immune Complexes in Erythema Multiforme and the Stevens-Johnson Syndrome

Early cutaneous lesions of erythema multiforme or mucosal lesions of the Stevens-Johnson syndrome contain delicate granular deposits of immune reactants and/or complement components lodged in the walls of vessels of the papillary dermis. Such deposits are not present in normal, unaffected skin although they can be caused to occur there by injection of substances which increase vascular permeability. Factors which cause accumulation of mononuclear cells in the papillary dermis have not been elucidated but we suggest that receptors for the C3d fragment of the third component of complement could be responsible. Factors which cause intercellular edema in the epidermis, epidermal-dermal separation, or necrotic keratinocytes are unknown. We, and others, may now measured immune complexes in the serum of patients experiencing these reaction patterns by means of Raji cell radioimmunoassay, C1q precipitation, 125I-C1q binding, cryoprecipitation and with monoclonal rheumatoid factor. Cryoimmunoglobulins have also been described and antigens of Herpesvirus hominus have been measured in the cryoprecipitate of 2 patients who experienced erythema multiforme following recurrent herpesvirus infection. Erythema multiforme commonly accompanied serum sickness reactions which occurred following injection of immune horse serum in the 1980s (von Pirquet and Schick). Such reactions are now well established as due to circulating immune complexes in antigen excess.

Suppressor T cells in tolerance to deaggregated horse anti-human thymocyte globulin in man.

To understand the mechanism by which deaggregated horse anti-human thymocyte globulin (dATG) fails to induce untoward immunological reactions in man, three patients who received ATG and two patients who received dATG were studied for evidence of sensitization or tolerance to the foreign globulin. The ATG but not the dATG recipients developed allergic or serum sickness reactions; antihorse serum antibody could be detected in their serum and their blood cells proliferated in vitro in the presence of horse serum and secreted antihorse serum antibodies (P less than 0.001). Tolerance of the dATG recipients was shown to be mediated by specific T suppressor cells that carry receptors for horse serum and could be detected in the blood of one patient, whom we have studied serially, 13 weeks after therapy. Deaggregated ATG does not induce allergic or serum sickness reactions. It induces tolerance to the foreign protein via the generation of specific short-lived suppressor cells.

Experimental immune pancreatitis in the mouse by rabbit immune sera directed against purified enzymes of the exocrine pancreas

An experimental xenogeneic immune pancreatitis was induced in AB-mice by repeated intraperitoneal injections of rabbit immune sera directed against purified pancreatic enzymes (alpha-amylase, lipase, trypsin) for 3 hours up to 8 days. Histologically, the immune pancreatitis is characterized by three different findings: 1. Multiple acinar cell necroses on the 2nd, 3rd and 5th day of immune serum application. 2. A dedifferentiating acinar cell atrophy with development of pseudocanalicular acini on the 5th and 9th day. 3. An increasing interstitial histiolymphoplasmocytic pancreatitis on the 5th and 9th experimental day. Ultrastructurally, the acinar cell necroses proved as the final stage of a step-by-step developing acute lethal cell damage. The dedifferentiating acinar cell atrophy corresponds to a chronic sublethal cell injury with alteration of different cytoplasmic components. The interstitial pancreatitis in immune serum treatment is characterized by differently activated histiocytes and lymphocytes as well as by mature plasma cells. Because of immune histological findings (peri- and intraacinar deposition of rabbit globulin, specific fixation of guinea-pig complement, and appearance of mouse globulin in the mouse exocrine pancreas) and control experiments with rabbit and mouse normal serum as well as with physiological saline, the pathogenesis of the induced xenogeneic immune pancreatitis is regarded as a twophase process: 1. The acinar cell necroses are mainly due to a cytotoxic immune reaction (possibly in combination with an immune complex reaction) caused by specific anti-pancreatic enzyme antibodies of the applied immune sera. The dedifferentiating acinar cell atrophy may be the result of a specific action of the anti-enzyme antibodies against the corresponding pancreatic enzymes in the apical secretion granules of the pancreatic acinar cells. 2. The interstitial histiolymphoplasmocytic pancreatitis is mainly the morphologic substrate of an extravascularly (intraperitoneally) induced serum sickness reaction (immune complex reaction) due to the foreign proteins applied with the xenogeneic immune sera.

Acute Exertional Rhabdomyolysis

To the Editor. —The article Acute Exertional Rhabdomyolysis by Drs. Demos and Gitin ( Arch Intern Med 133:233-239, 1974) prompts me to report a case of rhabdomyolysis with symptoms similar to an acute serum sickness reaction. Patient Summary. —A 24-year-old man had been well until November 1972 when, on awakening one morning, he noted severe pruritis followed by periorbital edema, a tightness in his throat (laryngal edema?), shortness of breath with a tightness in his chest that he described as an asthma attack, and arthralgia in the joints of his fingers. He was admitted to the hospital and was treated with diphenhydramine hydrochloride (Benadryl). His symptoms subsided in three days' time with this medication and with bed rest. There was no evidence of rash, fever, or weakness during this episode. He did state that about three days prior to the episode he exercised strenuously, but he also stated that he was

Section 14.—Serum Sickness and Drug Reactions

Section 14.—Serum Sickness and Drug Reactions

Serum sickness and drug reactions

Serum sickness and drug reactions

Section 14.--Serum Sickness and Drug Reactions

Section 14.--Serum Sickness and Drug Reactions

Cryotherapy for Snakebite

To the Editor:— I feel compelled to respond to the recent critical commentary by Bierly and Buckley (195:575, 1966). As I have stated before in print, the individuals who use cryotherapy properly in the treatment of snakebite swear by it, and those who do not use it condemn it to the high heavens. I have treated over 40 snakebites with this method and think it is a wonderful adjunct to other measures. The only death which we have had related to snakebite was that of a serum-sickness reaction from the horse serum in the antivenin. This cause of death was confirmed by autopsy findings. In every instance where we have given more than two ampules of antivenin, we have had a serum-sickness reaction which in many instances was more serious than the snakebite itself. The article by Bierley and Buckley will allow a great deal of medicolegal vulnerability to