Type III Hypersensitivity Reaction

Etiology

Serum sickness is caused by drugs containing a protein moiety of other species (heterologous protein), such as antivenins, vaccines, antitoxin, and streptokinase. The heterologous protein can act as an antigen triggering the immune response. Monoclonal and polyclonal antibodies prepared from rabbit, horse, or mouse serum-like anti-thymocyte globulin, OKT-3, have been found to cause type III hypersensitivity reactions.

Serum sickness-like reactions (SSLR) can be seen with synthetic monoclonal antibodies (chimeric protein). Infliximab, used in the management of rheumatoid arthritis and Crohn disease, and omalizumab, used to treat asthma, are known to be associated with SSLR.[3]

Stings from insects, ticks, and mosquito bites may cause serum sickness.[4]

Infectious diseases like hepatitis B and bacterial endocarditis present a continuous source of antigen to form circulating immune complexes.

Other examples of medications implicated in type III hypersensitivity reactions are cephalosporins, ciprofloxacin, furazolidone, griseofulvin, lincomycin, metronidazole, para-aminosalicylic acid, penicillin, streptomycin, sulfonamides, tetracycline, allopurinol, barbiturates, bupropion, captopril, carbamazepine, fluoxetine, and penicillamine.[5][6]

Epidemiology

The annual rate of serum sickness incidence is low. In one meta-analysis, the incidence of serum sickness following the administration of Crotalidae polyvalent immune Fab antivenom used for crotaline snake envenomation was 0.13%.[7] In another retrospective study, serum sickness-like reactions to equine and human-derived rabies immunoglobulin were rare under the age of 10 years at 0.05% and 0.01%, respectively.[8] A literature review of cefaclor-associated serum sickness-like disease found its incidence to be less than 0.2% per drug course, with most cases occurring in children aged less than five years.[9]

Further, the probability of developing serum sickness is dependent on the dose and varies by antigen type. For example, serum sickness associated with equine origin anti-rabies serum is more likely than tetanus antitoxin (16.3% vs. 2.5% to 5%).[10]

Pathophysiology

After exposure to antigen, an individual's immune system responds by creating antibodies after 4-10 days. The antibody reacts with the antigen, forming immune complexes that circulate and can diffuse into the vascular walls, where they may initiate fixation and activation of complement. These immune complexes, along with complement, produce an influx of polymorphonuclear leukocytes into the site, where tissue damage takes place by the release of proteolytic enzymes.[11][12] The process takes place in three steps:

1: Immune complex formation: Endogenous or exogenous antigen exposure triggers an antibody formation. Exogenous antigens are foreign proteins such as infectious microbes or pharmaceutical products. Endogenous antigens are self-antigens against which autoantibodies are generated (autoimmunity). In both cases, the antigens bind to antibodies, forming circulating immune complexes, later migrating out of plasma and depositing in host tissues.

2: Immune complex deposition: The pathogenicity of immune complexes is partly dependent on the antigen-antibody ratio. When the antibody is in excess, the complexes are insoluble, do not circulate, and are phagocytosed by macrophages in the lymph nodes and spleen. However, when the antigen is in excess, the aggregates are smaller. They freely filter out of circulation in organs where the blood is transformed into fluids such as urine and synovial fluid. Therefore, immune complexes affect glomeruli and joints.

3: Inflammatory reaction: After the deposition of the immune complexes, the final step is activating the classical pathway, leading to the release of C3a and C5a, which then recruit macrophages and neutrophils and causes inflammatory damage to tissues. Depending on the site, symptoms of vasculitis (blood vessels), arthritis (joints), or glomerulonephritis (glomeruli) develop.

History and Physical

The clinical manifestations of the immune-complex mediated disease depend on the type of antigen and route of exposure. For example, intravenous entry of antigen can lead to vasculitis, arthritis, and glomerulonephritis. Inhalational entry can manifest with a pulmonary syndrome termed hypersensitivity pneumonitis. Local injection of the antigen can cause necrotizing skin lesions called Arthus reaction. Immune-complex-associated inflammation of the vessels of the dermis and subcutaneous fat can have manifestations such as purpuric rash, erythema nodosum (tender red nodules on the anterior surface of lower extremities), or erythema multiforme (target lesions with minimal mucosal involvement, often present in lower extremities).

The history and physical examination findings of common immune complex-mediated diseases are described below.

Serum Sickness: Before the advent of antibiotics, horse serum was used to treat patients with scarlet fever and pneumonia. The host antibodies bind with the non-self antigens in horse sera to form immune complexes that deposit in the joints, subendothelial layer, and mesangium of the glomeruli. The classic symptoms of serum sickness are rash, arthritis, and fever. Proteinuria can be seen with renal involvement. Symptoms appear one to two weeks after exposure to the antigen. As the phagocytic system removes the immune complexes, in a few weeks, the symptom resolution ensues with an overall excellent prognosis. In modern times, serum sickness is associated with exposure to heterologous (nonhuman) protein (e.g., equine antisnake venom) or chimeric antibodies (rituximab/murine-rabbit chimeric anti-CD-20).[13] A serum sickness-like reaction (SSLR) consisting of fever, rash, and arthralgia can be caused by antigens present in drugs such as cefaclor and penicillin.[9] The precise mechanism of SSLR remains unclear; however, there could be a potential role of drug metabolites that are directly toxic to the cells. The features of serum sickness, such as vasculitis and glomerulonephritis, are not present in SSLR. 

Hypersensitivity Pneumonitis (HP): HP, also known as extrinsic allergic alveolitis, is a respiratory syndrome that involves the deposition of immune complexes in the alveoli, interstitium, terminal bronchioli, and lung parenchyma. The inhalation of antigen triggers an allergic immune response that is IgE-mediated.[14] However, specific allergens predominantly cause IgG response consistent with type III hypersensitivity disorder. The antigen can be a microbe, protein (plant or animal origin), or a chemical (organic and inorganic) present in the workplace or at home.[15] A well-studied entity of HP is the farmers' lung, where agricultural workers are exposed to the antigens from thermophilic molds (spores of Micropolyspora faeni and Thermoactinomyces Vulgaris) that grow on crops. Another example of HP is the bird fancier's disease, in which the etiologic bird-related antigens include immunoglobulins, intestinal mucin present in bird droppings, or waxy coating of the feathers.[16] 

A high index of suspicion is needed for the diagnosis of HP. A thorough history should be conducted to elicit the environmental and occupational exposure information of the patient.[17] In the acute phase (2-9 hours of antigen exposure), symptoms of fever, cough, and dyspnea may develop that peak within 24 hours. Re-exposure to the antigen can cause worsening dyspnea. In chronic exposure, weight loss is often present with respiratory symptoms. A physical examination may reveal inspiratory crackles, cyanosis, clubbing, or signs of right heart failure.

Systemic Lupus Erythematosus (SLE): SLE is an autoimmune disease with multisystem involvement. The condition is characterized by the presence of circulating IgG and IgM autoantibodies to host tissue components. In most cases, the antibodies are directed against the parts of the nucleus, such as double-stranded DNA, histone, and ribonuclear proteins. In some patients, autoantibodies against the cells, including platelets, erythrocytes, neutrophils, and lymphocytes, can be present. The autoantibodies against the phospholipid moiety of the prothrombin activator complex or cardiolipin can lead to a hypercoagulable state. Major clinical signs and symptoms spanning multiple organ systems are listed below:[18]

• General: Fever, weight loss, and fatigue
• Musculoskeletal: Arthralgias, arthritis, and myalgias
• Mucocutaneous: Malar (butterfly) rash with photosensitivity, oral ulcers, alopecia
• Cardiac: Pericarditis, endocarditis, myocarditis
• Vascular: Raynauds phenomenon, predominantly small vessel vasculitis manifesting as petechiae, purpura, and superficial ulcers 
• Pulmonary: Pleural effusion, cough, and dyspnea
• Gastrointestinal: Nausea, vomiting, abdominal pain
• Renal: Glomerulonephritis, nephrotic syndrome, asymptomatic hematuria or proteinuria, diminished renal function
• Hematological: Anemia, leukopenia, hemolysis, thrombosis, fetal loss in pregnancy
• Central Nervous System: Headaches, seizures, stroke
• The musculoskeletal, mucocutaneous, and pulmonary systems are most commonly involved in SLE.

Post Streptococcal Glomerulonephritis (PSGN): The glomerular deposition of immune complexes triggered by nephritogenic strains of group A beta-hemolytic streptococci causes PSGN. Symptoms are usually apparent between 1 and 3 weeks after a streptococcal throat infection or 3-6 weeks in cases of skin infection. The presenting features could include microscopic or gross hematuria, proteinuria, hypertension, edema, and elevation in serum creatinine.[19]

Evaluation

In serum sickness, a complete blood count (CBC) with a differential count may show neutropenia, eosinophilia, or thrombocytopenia. Hepatitis serologies can be performed to assess for hepatitis B infection. Inflammatory markers, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) are elevated. Complement consumption will result in low C3, C4, and CH50 levels. Urinalysis may show mild proteinuria. Skin lesions, when biopsied, may show leukocytoclastic vasculitis that is non-specific. There is no single test to diagnose serum sickness definitively. The diagnosis primarily rests on the temporal association of antigen exposure to classic clinical manifestations, such as fever, arthritis, and rash.

Peripheral eosinophil count is usually normal in HP. Total IgG levels are often elevated. Precipitating antibodies in the patient’s serum against the suspected causative agent can be tested, though this test has a low sensitivity. In the acute phase of HP, a chest X-ray can show patchy or homogeneous, bilateral interstitial and alveolar nodular infiltrates. In chronic cases, fibrotic changes are noted. A High-resolution CT scan (HRCT) has higher sensitivity than a chest X-ray and can help demonstrate the architectural changes in detail. Greater than 50% of lymphocytes in bronchoalveolar lavage are suggestive of HP. There is no gold standard test to diagnose HP.[20][15]

An evaluation of SLE may include CBC with a differential metabolic panel, complement levels, and confirming the presence of antibodies. ANA is sensitive and is almost a universal finding in SLE. Anti-dsDNA and anti-smith antibodies are specific to the diagnosis of SLE. The urinalysis with microscopy and urine spot protein to creatinine ratio must be ordered to evaluate for possible nephritis and quantification of proteinuria. A renal biopsy is needed for the definitive diagnosis and classification of lupus nephritis. Appropriate imaging studies are required for the evaluation of pulmonary and joint symptoms.

In PSGN, antibodies against streptolysin O, streptokinase, or deoxyribonuclease B can be elevated in up to 94.6% of cases.[21] Complement levels are low. Urinalysis with microscopy can determine proteinuria, hematuria, and RBC casts. A kidney biopsy may show proliferative changes on light microscopy; deposition of C3 and IgG in a diffuse granular pattern in the mesangium and glomerular capillary walls (starry sky appearance) noted on immunofluorescence; immune complex deposits evident as subepithelial humps on electron microscopy. Throat cultures are not a reliable test as only 10-20% of the patients who present with a sore throat in general clinical practice have a positive culture for group A Streptococcus.[22]

The common investigations relevant to the evaluation of immune complex-mediated diseases are summarized below:

Blood

• CBC with a differential count, complete metabolic panel
• Peripheral blood smear
• ESR, CRP
• Complement levels
• Quantitative serum immunoglobulins - IgG and IgM
• Hepatitis serology and serum cryoglobulins
• Antibody testing - ANA, anti-ds DNA, rheumatoid factor, anti-histones, anti-Smith, anti-(SS-A), anti-(SS-B), anti-RBC, antiplatelet, and anti-neutrophil antibodies
• Streptozyme test (measures five streptococcal antibodies) - antistreptolysin (ASO), antinicotinamide-adenine dinucleotidase (anti-NAD), antihyaluronidase (AHase), antistreptokinase (ASKase), anti-DNAse B antibodies

Urine

• Urinalysis with microscopy
• Urine spot protein/creatinine (PC) ratio
• 24 -hour urine protein

Imaging Studies

• X-ray
• CT scan

Allergic Skin Testing

• Skin prick tests are performed using various allergens from animals, food, plants, pathogens, and environmental pollutants.

Special Procedures

• Skin biopsy
• Renal biopsy
• Bronchoscopy

Cultures

• Blood cultures
• Skin culture
• Throat culture

Treatment / Management

Type III hypersensitivity reaction can be treated based on the clinical presentation:

• Removal of the offending agent is the mainstay of treatment of type III hypersensitivity reaction.[23]
• Antihistamines and nonsteroidal anti-inflammatory drugs can provide symptomatic relief.[24]
• Corticosteroids are used in severe cases to suppress inflammation. They are also used as premedication to prevent hypersensitivity from happening.[25]
• Avoiding exposure to an allergen is critical to the management of HP. In addition, corticosteroids are helpful in patients with inflammatory features.
• SLE is treated based on the individual patient's disease condition. Hydroxychloroquine is essential for long-term treatment in all SLE patients.[26] Antimalarials, corticosteroids, nonbiologic DMARDS, nonsteroidal anti-inflammatory, and biologic DMARDs are other medications used to treat SLE.
• The patient must be hospitalized in cases of hemodynamic instability, life-threatening symptoms, or unclear diagnosis.
• Many infectious and autoimmune diseases are linked to type III hypersensitivity reactions. A consultation with the rheumatologist, immunologist, and infectious disease specialist must be considered.
• Treatment of autoimmune disorders (e.g., SLE) includes one or a combination of hydroxychloroquine, NSAIDs, azathioprine, cyclophosphamide, methotrexate, mycophenolate, and tacrolimus.[27]
(B2)

Differential Diagnosis

Type I and II hypersensitivity reactions are antibody-mediated similar to type III hypersensitivity. Their clinical features can overlap. 

Type I or immediate hypersensitivity is mediated by preformed IgE antibodies that coat mast cells. The IgE antibodies are crosslinked by the free allergen (antigen), leading to mast cell degranulation and the release of histamine and inflammatory mediators. Examples of type I hypersensitivity mediated conditions are:

• Anaphylaxis
• Bronchial asthma
• Allergic rhinitis
• Food allergies

Type II hypersensitivity is mediated by IgG and IgM antibodies that coat (opsonize) the circulating cells (platelets, erythrocytes) with or without complement. With opsonization, the cells become the target for phagocytosis by macrophages and neutrophils or complement-mediated lysis. In other cases, the anti-receptor antibodies interfere with the normal function of the receptor (e.g., anti-acetylcholine receptor). Examples of type II hypersensitivity mediated conditions are:

• Autoimmune hemolytic anemia
• Autoimmune thrombocytopenic purpura
• Acute rheumatic fever
• Good pasture syndrome
• Myasthenia gravis
• Graves disease
• Pernicious anemia 
• ANCA vasculitis

Prognosis

The prognosis of type III hypersensitivity reaction depends on the disease and the underlying comorbidities. Serum sickness has an excellent prognosis. The symptoms usually resolve 1 to 2 weeks after the withdrawal of the offending agent. Hypersensitivity pneumonitis can have long-term morbidity with progressive symptoms. Poor prognostic indicators include prolonged or a higher intensity of exposure, older age, digital clubbing, and fibrotic changes in the lung.[15] Autoimmune diseases, e.g., SLE, are frequently associated with complications such as hypertension, renal failure, and infections. 40% to 75% of patients with SLE develop lupus nephritis; 10% progress to ESRD.[28][29] The 5, 10, and 15-year survival rates are near the 96, 93, and 76% range, respectively.[30]

Complications

Some of the complications associated with type III hypersensitivity reaction include:

 Serum Sickness

• Vasculitis
• Acute kidney injury, glomerulonephritis

Hypersensitivity Pneumonitis

• Alveolitis
• Pulmonary fibrosis/restrictive lung disease
• Cor pulmonale

SLE

• Hypertension 
• Infections
• Thrombosis
• Glomerulonephritis, end-stage renal disease
• Miscarriage

Post-streptococcal Glomerulonephritis

• Acute kidney injury requiring dialysis
• Chronic kidney disease
• Proteinuria
• Hypertension