Type III Hypersensitivity Reaction

Etiology

Soluble immune complexes or aggregates of antigen and antibody not cleared by the body and subsequently deposited in tissues, triggering inflammation and damage, are the underlying cause of type III hypersensitivity reactions. Common etiologies include infections such as Streptococcus pyogenes, hepatitis B, hepatitis C, and bacterial endocarditis, as well as exposure to foreign proteins in medications, vaccines, antivenoms, and insect stings, or in the setting of autoimmune diseases.[3] Some common diseases mediated by type III hypersensitivity include the following:

• Arthus reaction
• Hypersensitivity pneumonitis
• IgA nephropathy
• IgA vasculitis
• PSGN
• Rheumatoid arthritis
• Secondary polyarteritis nodosa (PAN)
• Serum sickness
• SLE

The administration of heterologous, or nonhuman, serum proteins, followed by the subsequent illness caused by the formation of immune complexes, underlies the etiology of serum sickness. Common causes of serum sickness are antivenoms, anti-toxins, streptokinase, anti-thymocyte globulin, the human diploid cell rabies vaccine, rituximab, and infliximab.[4][5][6] Clinicians should not confuse serum sickness with serum sickness-like reactions, which are clinically similar but not mediated by immune complexes. Common causes of serum sickness-like reactions are vaccines, infections, and medications such as penicillin, amoxicillin, cefaclor, and trimethoprim-sulfamethoxazole.[7][8]

Epidemiology

The incidence of type III hypersensitivity reactions varies widely depending on the underlying trigger, patient factors, and type of exposure. Serum sickness can develop after antivenom or monoclonal antibody therapy, with rates influenced by dose, antigen properties, prior sensitization, and conditions such as hypergammaglobulinemia or cryoglobulinemia. For example, serum sickness occurs in approximately 13% of patients treated with Crotalidae polyvalent immune Fab antivenom, but can reach 44% to 61% with older antivenin preparations.[9][10][11][12] Additionally, serum sickness occurs in 6% to 20% of patients treated with rituximab, especially in women and those with rheumatologic disease and hepatitis C-related mixed cryoglobulinemia.[13]

Autoimmune disorders such as SLE, with an incidence of 1 to 25 per 100,000, and rheumatoid arthritis, with a worldwide prevalence of 0.2% to 1% are also linked to immune complex–mediated disease.[14][15] PSGN remains the leading cause of childhood acute glomerulonephritis worldwide. Nearly 97% of new cases occur in areas with poor socioeconomic status, with a higher prevalence in males, patients older than 60, and children between 5 and 12.[16] Hypersensitivity pneumonitis affects 0.4% to 7% of farmers and up to 21% of pigeon breeders annually. Additionally, hepatitis B may account for up to one-third of cases of PAN.[17] IgA vasculitis is primarily a disease of childhood, with the highest incidence in children between 3 and 15, and an annual incidence of 10 to 20 per 100,000 children and 5 per 100,000 adults.[18][19]

Pathophysiology

Antigen–antibody immune complexes that form in circulation and subsequently deposit in tissues, triggering inflammation and tissue injury, mediate type III hypersensitivity reactions. Following exposure to an antigen, the immune system produces IgG or IgM antibodies within 7 to 10 days. These antibodies bind to endogenous or exogenous (eg, pathogens or drugs) soluble antigens, forming circulating immune complexes. When not cleared efficiently, these complexes deposit in tissues such as glomeruli, synovia, blood vessels, or alveoli, initiating type III hypersensitivity reactions.[20][21] The 3 key steps of type III hypersensitivity reactions are as follows:

• Formation: In antigen excess, small soluble immune complexes form. Unlike large complexes, macrophages do not efficiently clear small immune complexes, and they persist in circulation.
• Deposition: Due to ineffective macrophage clearance, complement depletion, and phagocyte overload, small and larger immune complexes deposit in tissues.
• Inflammation: Deposited complexes, primarily medium-sized, activate the classical complement pathway, generating C3a and C5a, which increase vascular permeability and recruit neutrophils and monocytes. Activated leukocytes release proteolytic enzymes and reactive oxygen species, while platelets aggregate and promote microthrombi, collectively causing tissue damage.

Clinically, this manifests as vasculitis, arthritis, or glomerulonephritis, depending on the site of immune complex deposition. PSGN results from glomerular deposition of immune complexes formed in response to nephritogenic strains of S pyogenes.[22] SLE is a prototypical systemic autoimmune disease driven by circulating immune complexes formed by IgG and IgM autoantibodies that target nuclear antigens, such as double-stranded DNA (dsDNA), histones, and ribonucleoproteins. Immune complex deposition leads to widespread tissue inflammation and damage in multiple organ systems.[23]    

Hypersensitivity pneumonitis, also known as extrinsic allergic alveolitis, occurs due to repeated inhalation of environmental antigens such as microbial spores or animal proteins, causing IgG-mediated immune complex deposition in alveolar and interstitial tissues.[24] Notable causes include thermophilic molds like Micropolyspora faeni in farmer’s lung and bird-derived proteins in bird fancier’s disease.[25][26] Patients with hepatitis B may develop PAN due to antibodies formed against the hepatitis B surface antigen. Immune complexes deposit in medium-sized blood vessel walls, causing the symptoms associated with PAN. An Arthus reaction involves the formation of immune complexes within the small blood vessels of the skin at the injection site of a booster vaccine.

History and Physical

Arthus Reaction

An Arthus reaction presents as painful local swelling and erythema that typically occurs within a few hours at the site of a vaccine booster. Symptoms typically peak within 24 hours, and if severe, can cause localized skin necrosis.[27]

Hypersensitivity Pneumonitis

The symptoms of hypersensitivity pneumonitis may range from acute fever, dyspnea, and cough occurring within hours of antigen exposure to chronic manifestations such as progressive dyspnea, weight loss, digital clubbing, and pulmonary fibrosis.[28]

IgA Nephropathy

Clinicians should suspect IgA nephropathy in patients who experience recurrent episodes of gross hematuria, particularly following an upper respiratory infection. It may also present as persistent microscopic hematuria with or without proteinuria and a gradual decline in kidney function. Some patients report flank pain or low-grade fever, while less commonly the disease manifests with acute kidney injury or nephrotic syndrome.

IgA Vasculitis

The classic tetrad of IgA vasculitis includes palpable purpura without thrombocytopenia or coagulopathy, arthritis or arthralgia, abdominal pain, and kidney disease. Typically, purpura and joint pain are the initial presenting symptoms.[29][30] Gastrointestinal bleeding can also occur in 20% to 30% of patients. See StatPearls' companion topic, "IgA Vasculitis (Henoch-Schönlein Purpura)," for an in-depth discussion regarding IgA vasculitis. 

Post-Streptococcal Glomerulonephritis

PSGN typically presents 1 to 3 weeks after streptococcal pharyngitis or 3 to 6 weeks after impetigo. Most children are asymptomatic. Symptomatic patients can present with microscopic hematuria or nephritic syndrome marked by red or brown urine, proteinuria, periorbital edema, hypertension, and elevated creatinine.[19] See StatPearls' companion topic, "Post-Streptococcal Glomerulonephritis," for a complete discussion regarding PSGN.

Rheumatoid Arthritis

The classic symptoms of rheumatoid arthritis are a gradual onset of symmetric joint pain and swelling, most pronounced in the small joints of the hands, wrist, and forefoot, morning stiffness, and decreased grip strength. Please see StatPearls' companion topic, "Rheumatoid Arthritis," for further information regarding rheumatoid arthritis.

Secondary Polyarteritis Nodosa

Symptoms of PAN associated with hepatitis B and, less often, hepatitis C are systemic and often involve multiple organs. Initially, patients may present with fever, fatigue, weight loss, and muscle or joint pain. As arterial damage progresses, manifestations may include purpura, skin nodules and ulcers, peripheral neuropathy such as mononeuritis multiplex, and abdominal pain due to mesenteric ischemia. Renal involvement is also common. See StatPearls' companion topic, "Polyarteritis Nodosa," for a detailed discussion regarding the clinical presentation of polyarteritis nodosa.[28]  

Serum Sickness

The symptoms of serum sickness begin 1 to 2 weeks after the initial exposure to the offending agent, and within 1 to 7 days after a previous exposure. In some, the reaction may be immediate if IgE or IgG antibodies are still present from a previous exposure. Almost all patients develop a fever higher than 101.3 °F (38.5 °C ) that often spikes and normalizes on the same day. Additional features are a pruritic urticarial or serpiginous rash with a dusky, bruised center that lasts a few days to 2 weeks following discontinuation of the offending agent. The rash typically begins at the site of drug administration and spares the mucus membranes. Arthralgias are also common. Other less common manifestations may be headache, edema, lymphadenopathy, nephropathy, vasculitis, and gastrointestinal symptoms.[29] See StatPearls' companion topic, "Serum Sickness," for additional information regarding the clinical presentation of serum sickness.

Systemic Lupus Erythematosus

Patients with SLE present with a wide variety of symptoms. Fever, fatigue, myalgia, and weight loss are common, as are polyarticular arthritis, a malar rash, painless oral or nasal ulcers, pericarditis, and Raynaud phenomenon. Glomerulonephritis, pleuritis, stroke, seizures, cognitive dysfunction, anemia, leukopenia, thrombocytopenia, and keratoconjunctivitis sicca are additional characteristic features. See StatPearls' companion topic, "Systemic Lupus Erythematosus," for further discussion regarding SLE.

Evaluation

The evaluation of type III hypersensitivity reactions requires a methodical diagnostic approach combining physical examination, detailed exposure history, serologic, histopathologic, and imaging studies tailored to the clinical context.

Arthus Reaction

Clinicians primarily diagnose an Arthus reaction based on clinical findings. In some cases, measurement of serum vaccine-specific IgM and IgG antibodies can identify a hyperimmunized state. CRP and ESR frequently rise during the reaction.

Hypersensitivity Pneumonitis

Laboratory evaluation in patients with suspected hypersensitivity pneumonitis has limited value. Testing for specific IgG antibodies has a high rate of positive tests among exposed asymptomatic patients and a high rate of false-negative results. Antinuclear antibodies, rheumatoid factor, and cyclic citrullinated peptide antibodies are helpful to exclude subclinical rheumatologic disease. In the presence of pulmonary hemorrhage, antiglomerular basement membrane antibodies, antineutrophil cytoplasmic antibodies, antiphospholipid antibodies, and antistreptococcal antibodies are additional warranted laboratory tests. Pulmonary function tests (PFT) help determine the pattern and severity of the respiratory dysfunction. While PFTs typically reveal an obstructive pattern, affected patients may also have an obstructive or mixed restrictive-obstructive pattern. High-resolution computed tomography (HRCT) is the imaging study of choice for suspected hypersensitivity pneumonitis. In nonfibrotic disease, HRCT typically demonstrates widespread, bilateral, poorly defined centrilobular nodules or ground-glass opacities, often accompanied by lobular areas of decreased attenuation, reduced vascularity, and expiratory air-trapping. In contrast, irregular linear opacities or coarse reticulation with associated lung distortion, which may appear diffusely or predominate in the mid-lung zones, mark fibrotic hypersensitivity pneumonitis. Findings of small airway disease must be present on HRCT for the results to be consistent with hypersensitivity pneumonitis.[31] For patients in whom the initial diagnostic evaluation is unclear, a bronchoalveolar lavage with greater than 50% lymphocytes is suggestive of hypersensitivity pneumonitis.[25]

IgA Nephropathy

Though not required in all patients, confirmation of IgA nephropathy is through a kidney biopsy with immunofluorescence or immunoperoxidase staining. Results reveal predominantly IgA deposition. Additional evaluation, to investigate secondary causes such as liver disease, HIV infection, and monoclonal gammopathy of renal significance, depends on the patient's presentation. 

IgA Vasculitis

The diagnosis of IgA vasculitis is primarily clinical, based on the presence of palpable purpura of the lower extremities and buttocks in the absence of thrombocytopenia or coagulopathy, plus 2 or 3 of the following clinical features:

• Arthritis or arthralgia;
• Abdominal pain; and
• Kidney disease.[32][33]

Clinicians biopsy the affected organ, such as the kidney or the skin, in patients with atypical presentations. The presence of leukocytoclastic vasculitis and a predominance of IgA deposition confirms the diagnosis. Additional studies include a platelet count, PT, PTT, and bleeding time to exclude other diagnoses that cause purpura. Urinalysis and serum creatinine evaluate the level of kidney involvement. Imaging, such as plain radiographs and ultrasound, may be necessary for abdominal and testicular pain.

Post-Streptococcal Glomerulonephritis

Clinical findings of acute nephritis, marked by hematuria with or without RBC casts, proteinuria, edema, oliguria, and hypertension, and documentation of a recent group A ß-hemolytic streptococcal infection typically establish the diagnosis of PSGN. Throat cultures have limited utility, with positivity in only 10% to 20% of patients.[34] In 94.6% of cases, elevated streptococcal antibody titers such as anti-streptolysin O, anti-streptokinase, and anti-DNase B are present.[35][36] C3 and CH50 will also be low; however, this finding is not specific for PSGN, as patients with membranoproliferative glomerulonephritis also have low complement levels. Renal biopsy may demonstrate proliferative glomerulonephritis, with granular deposits of IgG and C3 known as the "starry sky" pattern on immunofluorescence as well as subepithelial humps on electron microscopy. 

Rheumatoid Arthritis

In addition to physical examination findings, the evaluation of rheumatoid arthritis begins with measuring both rheumatoid factor and anti-citrullinated peptide antibodies. Plain radiographs of the hands and feet can help establish the diagnosis and monitor disease progression over time. Early radiographs may be normal or reveal only soft tissue swelling and periarticular osteopenia. As the disease progresses, symmetric joint space narrowing, bone erosions, and possibly joint subluxation confirm the diagnosis. Ultrasound or magnetic resonance imaging is helpful when clinicians are unable to detect synovitis due to the patient's body habitus or in the event of joint inaccessibility. Clinicians often use the 2010 American College of Rheumatology/European League Against Rheumatism diagnostic criteria to establish the diagnosis of rheumatoid arthritis. Chest radiograph, eye examination, and tuberculosis screening are necessary before beginning treatment with methotrexate, hydroxychloroquine, biologics, and Janus kinase inhibitors. Please see StatPearls' companion topic, "Rheumatoid Arthritis," for an in-depth discussion regarding rheumatoid arthritis.

Secondary Polyarteritis Nodosa

The diagnosis of PAN is clinical. Laboratory evaluation helps determine the extent of organ involvement and investigate the differential diagnoses. Initial laboratory tests include a CBC, serum creatinine, muscle enzyme concentrations, liver function studies, hepatitis B and C serologies, and a urinalysis. A chest radiograph helps exclude other vasculitides that primarily affect the lungs. Blood cultures are necessary to exclude endovascular infection. Additional potential testing depends on patient presentation and potential differential diagnoses. Possible tests include antineutrophil cytoplasmic antibodies, antinuclear antibodies, C3 and C4, cryoglobulins, serum and urine electrophoresis, HIV testing, testing for adenosine deaminase 2 deficiency, and VEXAS syndrome. A positive antineutrophil cytoplasmic antibody suggests ANCA-associated vasculitides, whereas a positive ANA suggests underlying SLE or systemic sclerosis. Ideally, a biopsy of the affected organ, revealing inflammation of the medium-sized arteries, should confirm the diagnosis. 

Serum Sickness

In serum sickness, a CBC may reveal neutropenia, eosinophilia, or thrombocytopenia. Elevated ESR and CRP levels are common, reflecting systemic inflammation—complement consumption results in low serum C3, C4, and CH50. Urinalysis may reveal mild proteinuria, and skin biopsies typically show leukocytoclastic vasculitis. Diagnosis primarily depends on the temporal relationship between antigen exposure and the classical triad of fever, rash, and arthritis, rather than a single confirmatory test.[22][35]

Systemic Lupus Erythematosus 

The evaluation of SLE involves a combination of laboratory and imaging studies to assess systemic involvement and guide management. The CBC may reveal hematologic abnormalities such as leukopenia, neutropenia, and thrombocytopenia. At the same time, an elevated creatinine, abnormal urinalysis with hematuria, pyuria, proteinuria, or casts, and a high urine protein-to-creatinine ratio suggest renal involvement. Elevated creatine kinase may indicate myositis, and hypergammaglobulinemia on serum protein electrophoresis reflects systemic inflammation. Serologic testing is central: ANA is almost always positive during the disease course; anti-dsDNA antibodies are present in about 70% of cases; and anti-Sm, anti-RNP, anti-Ro/SSA, and anti-La/SSB antibodies occur with varying frequencies and overlap with other connective tissue diseases. Titers of anti-dsDNA antibodies vary with disease activity, making them good indicators of disease activity and treatment response.[37] Clinicians detect antiphospholipid antibodies, including lupus anticoagulant, anticardiolipin, and anti-β2 glycoprotein I, in up to 40% of patients. These antibodies confer increased risks of thrombosis and pregnancy morbidity.[38] Complement, C3, C4, and CH50 levels are often low. At the same time, elevated ESR and CRP may be present. Clinicians should also check thyroid function and thyroid autoantibodies, given the increased risk of coexisting autoimmune thyroid disease.[39] When necessary, imaging studies such as renal ultrasound, echocardiography, MRI, or plain radiographs evaluate renal, cardiac, neurologic, pulmonary, or joint involvement.[40].

Treatment / Management

Management of type III hypersensitivity centers on removing the inciting antigen, dampening immune-complex–driven inflammation, and protecting organs.[41]

Hypersensitivity Pneumonitis

For patients with hypersensitivity pneumonitis, avoidance of antigen exposure, such as avian proteins and mold spores, is the cornerstone of management. Corticosteroids are used in acute or subacute inflammatory presentations when antigen avoidance is unsuccessful in controlling the condition. Patients who do not respond to antigen avoidance and glucocorticoids can undergo a trial of azathioprine or mycophenolate mofetil. The antifibrotic agent, nintedanib, helps prevent the progression of fibrosis. Supportive care involves seasonal influenza and pneumococcal vaccinations, pulmonary rehabilitation, and supplemental oxygen as needed. Patients with advanced lung disease may require lung transplantation. 

IgA Nephropathy

The management of IgA nephropathy begins with lifestyle modifications, including dietary sodium and protein restriction, weight control, smoking cessation, and exercise. Additionally, lipid management is also essential. Patients with IgA nephropathy and proteinuria levels of 0.5 g/d or higher should receive an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Patients with progressive disease or who are at high risk of progressive disease should receive immunosuppressive therapy with systemic glucocorticoids, targeted-release budesonide, or mycophenolate mofetil. Patients who do not receive immunosuppressive therapy and continue to have proteinuria exceeding 0.5g/d despite treatment with an ACE inhibitor or ARB for at least 3 months may benefit from the addition of an SGLT2 inhibitor such as dapagliflozin or empagliflozin. Endothelin receptor antagonists and dual endothelin angiotensin receptor antagonists such as sparsentan and atrasentan are additional alternatives.

IgA Vasculitis

Most patients with IgA vasculitis only require hydration, rest, and analgesics. NSAIDs or acetaminophen treat the pain associated with IgA vasculitis. Patients with severe abdominal or joint pain that does not respond to NSAIDs or that interferes with the patient's ability to eat, drink, or carry out their activities of daily living should receive glucocorticoids; otherwise, because they do not alter the disease course, glucocorticoids are not routinely used to treat symptoms of IgA vasculitis.

Immunosuppressive therapy is necessary in children who present with proteinuria in excess of 1g/d or impaired kidney function during the acute episode. Initial therapy consists of glucocorticoids for 3 months. If the level of proteinuria continues to exceed 0.5 g/d, clinicians repeat a kidney biopsy and begin a 3-month course of therapy with an ACE inhibitor or ARB. If evidence of active inflammation exists on the kidney biopsy, then the child receives an additional 3 months of glucocorticoids.

All adults who develop proteinuria in excess of 0.5 g/d receive an ACE inhibitor or ARB. Disease progression or development of proteinuria of 1g/d or higher prompts a repeat kidney biopsy.[42] Adults with proteinuria of 1g/d or higher receive a 6-month trial of systemic glucocorticoids in addition to an ACE inhibitor or ARB. Persistent proteinuria or worsening creatinine warrants a repeat kidney biopsy. Adults with continued active inflammation on repeat kidney biopsy should receive mycophenolate or cyclophosphamide. Those with no active inflammation wean from glucocorticoids and continue the ACE inhibitor or ARB.(A1)

Post-Streptococcal Glomerulonephritis

Patients with PSGN and the presence of an ongoing streptococcal infection should receive penicillin or erythromycin if penicillin allergic. The remainder of care is supportive, focusing on treating the complications. Sodium and water restriction, as well as loop diuretics, treat volume overload, pulmonary edema, and hypertension. In the event hypertensive encephalopathy develops, clinicians use oral nifedipine or IV nicardipine. Severe renal impairment manifesting as uremia, defined as a BUN between 89 and 100 mg/dL, volume overload unresponsive to therapy, or a serum or plasma potassium greater than 6.5 mEq/L, unresponsive to medical therapy, warrants dialysis.

Rheumatoid Arthritis

The treatment of rheumatoid arthritis centers around controlling synovitis, preventing joint damage, relieving pain, and preserving musculoskeletal function. Regular physical activity is imperative, and patients should receive proper instruction from a physical therapist and occupational therapist about specific movements that will increase strength and mobility without worsening joint inflammation. Unless contraindicated, all patients with rheumatoid arthritis should receive the disease-modifying antirheumatic drug (DMARD) methotrexate as well as NSAIDs or glucocorticoids as needed for symptomatic relief. Patients who fail methotrexate alone may try triple therapy with methotrexate, hydroxychloroquine, and sulfasalazine or add a tumor necrosis factor (TNF) such as etanercept to methotrexate. If a TNF is inappropriate, then methotrexate plus abatacept, a cytotoxic T-lymphocyte antigen-4, tocilizumab, a humanized IgG1 anti-human IL-6 receptor antibody, leflunomide, or sarilumab, a human monoclonal antibody directed against the membrane-bound and soluble IL-6R, are acceptable alternatives.[43] Methotrexate plus rituximab or a Janus kinase inhibitor, such as tofacitinib, are less commonly used combinations.(A1)

Secondary Polyarteritis Nodosa

Patients with hepatitis associated PAN should receive treatment with antivirals as initial treatment. Patients with severe or persistent disease may require systemic glucocorticoids or an immunosuppressant medication; however, clinicians should monitor the status of the underlying infection. Clinicians can use plasma exchange as an alternative for patients with progressive disease who cannot receive immunosuppressive therapy. If an immunosuppressant is necessary, first-line choices are azathioprine or methotrexate. 

Serum Sickness

Antihistamines and NSAIDs provide symptomatic relief of mild systemic symptoms such as arthralgia, rash, or low-grade fever associated with serum sickness.[44] In moderate to severe cases, systemic corticosteroids are helpful to reduce immune-complex–driven inflammation. While patients should avoid reexposure to the offending agent, premedication with antihistamines and steroids may also prevent recurrence if reexposure is necessary in the future.[45] 

Systemic Lupus Erythematosus 

SLE requires a tailored, multi-agent approach. Patients should understand the importance of photoprotection and avoid smoking, as it increases the risk of active disease. They should also receive necessary immunizations before starting immunosuppressive medications and undergo routine monitoring of vitamin D levels, considering the need for sun avoidance. All patients benefit from hydroxychloroquine for disease control and reduction of flares.[46] Additionally, NSAIDs and a short course of glucocorticoids may be necessary in patients with mild disease. Those with moderate disease may require a longer course of glucocorticoids until the full effect of hydroxychloroquine is evident. Patients with severe, organ-threatening disease often require a short course of high-dose glucocorticoids in combination with mycophenolate, cyclophosphamide, or rituximab.[47] (B2)

Differential Diagnosis

 The following list outlines conditions commonly considered in the differential diagnosis of immune complex–mediated disease.

• Acute annular urticaria (urticaria multiforme)
• Acute hemorrhagic edema of infancy
• Acute postinfectious glomerulonephritis due to infections other than Streptococcus
• Alport syndrome
• Atherosclerosis
• Benign familial hematuria
• Byssinosis
• Catastrophic antiphospholipid syndrome
• C3 glomerulopathy
• Cholesterol crystal emboli
• Cryoglobulinemic vasculitis
• Degos disease
• Disseminated gonococcal or meningococcal infection
• Disseminated intravascular coagulation
• Drug reaction with eosinophilia and systemic symptoms
• Drug-induced vasculitis
• Ehlers–Danlos syndrome
• Embolic disease, such as an atrial myxoma, cholesterol, or septic emboli
• Endocarditis-associated glomerulonephritis
• Ergotism
• Erythema multiforme
• Fabry disease
• Fibromuscular dysplasia
• Granulomatosis with polyangiitis
• Hepatitis B or C vasculitis
• HIV vasculopathy
• Hypersensitivity vasculitis
• Infective endocarditis–associated immune complex disease
• Juvenile idiopathic arthritis
• Kawasaki disease
• Levamisole-adulterated cocaine vasculitis
• Leprosy-associated immune complex nephritis
• Lyme disease
• Malaria-associated nephropathy
• Malignant hypertension
• Microscopic polyangiitis
• Mixed connective tissue disease vasculitis
• Monoclonal gammopathy–related renal disease
• Mycotic aneurysm with distal embolization
• Necrotizing arachnidism
• Purpura fulminans
• Radiation fibrosis
• Rheumatic fever
• Rocky Mountain spotted fever
• Scarlet fever
• Segmental arterial mediolysis
• Serum sickness–like reactions
• Septic arthritis
• Sjögren syndrome–related vasculitis
• Stevens-Johnson syndrome and toxic epidermal necrolysis
• Syphilis immune complex vasculitis
• Toxic synovitis
• Thrombotic microangiopathies such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

   

Prognosis

The prognosis of type III hypersensitivity-related illnesses varies widely depending on the underlying condition, extent of immune complex–mediated injury, and success of eliminating the inciting antigen. Hypersensitivity pneumonitis demonstrates the most significant prognostic variability: patients with acute or subacute inflammatory forms often recover fully with antigen avoidance, while those who develop chronic fibrotic hypersensitivity pneumonitis face progressive, irreversible lung disease with significantly reduced survival and the potential need for lung transplantation.[25] IgA nephropathy follows a heterogeneous course, with some patients maintaining stable renal function for many years, while 10% to 30% progress to end-stage kidney disease within 10 years, particularly in the presence of proteinuria, hypertension, or reduced baseline renal function.[48] 

IgA vasculitis is usually self-limited in children, resolving within weeks, though adults have a higher risk of chronic kidney disease when nephritis is present. Serum sickness generally has an excellent prognosis, with symptoms resolving in days to weeks following antigen removal; chronic sequelae are rare. In contrast, SLE is a chronic, relapsing illness in which prognosis depends on organ involvement. Lupus nephritis, neuropsychiatric lupus, and cardiovascular disease remain leading causes of morbidity and mortality. However, survival has markedly improved with modern therapies.[49][50][51] Similarly, rheumatoid arthritis carries an increased risk of all-cause mortality, primarily due to cardiovascular disease, neoplasm, and respiratory illness. However, aggressive immunomodulation has improved outcomes.[52] The Arthus reaction is localized and self-limited, resolving once antigen exposure ceases, with an excellent prognosis. Finally, PSGN in children usually has a favorable outcome with a full recovery of renal function, but adults face a higher risk of persistent proteinuria, hypertension, and chronic kidney disease.

Complications

Complications resulting from type III hypersensitivity reactions arise from immune complex deposition and complement-mediated inflammation, leading to multisystem tissue injury. Additionally, patients face the risk of treatment-related complications such as diabetes, hypertension, immunosuppression, weight gain, osteoporosis, cataracts, and adrenal insufficiency related to glucocorticoid use or increased risk of infection and malignancy associated with the use of immunosuppressants. The most severe complication associated with an Arthus reaction is tissue necrosis, leading to skin ulceration, local hemorrhage, and possible infection. Patients with hypersensitivity pneumonitis can develop pulmonary fibrosis, hypoxia, and cor pulmonale as a result of pulmonary hypertension.

IgA nephropathy can lead to end-stage renal disease, which carries a significant number of associated complications, such as an increased risk of death from cardiovascular disease, hypertension, pericarditis, anemia, and electrolyte disturbances. Additionally, IgA vasculitis may cause long-term kidney disease, hypertension, gastrointestinal bleeding, intussusception, bowel ischemia, bowel perforation, or pancreatitis. While most patients with PSGN have minimal adverse sequelae, some can develop hypertension, recurrent proteinuria, and gradually progressive renal insufficiency.

Rheumatoid arthritis has a myriad of associated complications, both disease- and medication-induced. Hematologic complications include anemia, leukopenia, thrombocytopenia, Felty syndrome, and lymphoproliferative disorders, such as lymphoma and large granular lymphocyte leukemia. Depression, osteopenia, periodontal bone loss, muscle weakness, skin ulcers, lung disease, heart disease, mononeuritis multiplex, symmetric polyneuropathy, and carpal tunnel syndrome are some additional long-term effects. SLE carries a high risk of glomerulonephritis, arterial and venous thrombosis, cardiac disease, pregnancy loss, pulmonary hypertension, pulmonary hemorrhage, pneumonitis, progression to end-stage renal disease, and macrophage activation syndrome. Whereas, patients with severe serum sickness may develop peripheral neuropathy, including Guillain-Barré syndrome, vasculitis, acute kidney injury, and anterior uveitis.[53] These outcomes underscore the importance of early recognition and targeted immunomodulatory therapy to limit long-term organ damage.