Systemic Lupus Erythematosus Following Human Papillomavirus 9-Valent Vaccination
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology that can affect any organ in the body. Human papillomavirus (HPV) infection has been associated with the development of cervical dysplasia and cancer in SLE patients. HPV vaccines, including the 9-valent HPV vaccine (HPV9), are effective in preventing HPV infection and related diseases. While HPV vaccination is generally considered safe and immunogenic for SLE patients, concerns have been raised regarding the potential for autoimmune reactions, including the onset of SLE, following vaccination. This article presents two cases of SLE diagnosed after HPV9 vaccination and reviews the literature to explore the clinical characteristics of such cases and the safety of HPV vaccines, particularly HPV9.
Case Presentations
Case 1
A 21-year-old woman developed dizziness, fatigue, nausea, and vomiting five days after her first dose of the HPV9 vaccine. Over the next four days, she experienced cough, yellow phlegm, and chest tightness. Eighteen days post-vaccination, she was admitted to the hospital with a fever. Her medical and family histories were unremarkable, and she had no history of contact with cattle, sheep, or other relevant animals.
Laboratory tests revealed anemia, leukopenia, thrombocytopenia, hypocomplementemia, low serum albumin, elevated erythrocyte sedimentation rate (ESR), a positive direct Coombs test, and proteinuria of 1.64 g/day. Serum creatinine and C-reactive protein (CRP) levels were normal. Autoantibody screening showed high titers of antinuclear antibodies (ANA: 1:1000) and anti-double-stranded DNA antibodies (anti-dsDNA: 1:5), along with positivity for anti-nucleosome antibodies, anti-histone antibodies, and lupus anticoagulant. Antiphospholipid antibody testing was negative. Infection serology tests were positive for human Brucella IgG, herpes simplex virus IgG and IgM, rubella virus IgG, toxoplasma IgG, cytomegalovirus (CMV) IgG and IgM, and Epstein-Barr virus (EBV) IgG, but negative for EBV IgM, EBV-DNA, and CMV-DNA. Sputum culture revealed gram-positive cocci.
Chest computed tomography (CT) showed increased patch shadows and nodules in both lungs compared to a scan six days prior. A small amount of pleural effusion was present bilaterally, with a slight increase on the right side, and a small pericardial effusion was noted.
The patient was diagnosed with SLE and pulmonary infection and treated with methylprednisolone, intravenous immunoglobulin (IV Ig), antiviral drugs, and antibiotics. Although her fever, cough, and yellow phlegm resolved, her anemia and thrombocytopenia worsened, and she developed erythrocyte fragmentation, elevated D-dimer, and increased serum creatinine. She was diagnosed with thrombotic microangiopathy and treated with plasma exchange. Unfortunately, she experienced epilepsy and mental abnormalities during treatment, and magnetic resonance imaging (MRI) and cerebrospinal fluid tests confirmed neuropsychiatric SLE. Despite treatment with intravenous pulse methylprednisolone, her condition deteriorated, leading to secondary left heart failure, a new infection, and eventual death from multiple organ failure.
Case 2
A 21-year-old woman was admitted to the hospital with an intermittent fever that began six days after her first dose of the HPV9 vaccine. Her medical history included Raynaud phenomenon and a thyroid nodule, and her mother had been diagnosed with thyroid papillary carcinoma. The patient had no history of contact with cattle, sheep, or other animals.
Laboratory tests revealed anemia, leukopenia, low serum albumin, low complement (C3) levels, elevated ESR, a positive direct Coombs test, proteinuria of 0.94 g/day, and a normal CRP level. Microscopic examination of urine erythrocytes found 25 to 30/HPF, with 80% polymorphism in urinary erythrocyte morphology. Autoantibody screening showed high titers of ANA (1:1000) and anti-dsDNA (1:5) antibodies, along with positivity for anti-RNP, anti-SSA, anti-SSB, anti-centromere, anti-nucleosome, anti-histone, anti-b2 glycoprotein I, and anticardiolipin antibodies. Anti-Smith antibody testing was negative. Infection serology tests were positive for human Brucella IgG, herpes simplex virus IgG and IgM, rubella virus IgG, toxoplasma IgG and IgM, CMV IgM, and EBV IgM, but negative for EBV-DNA, CMV-pp65, and influenza virus RNA.
A kidney biopsy revealed Class IV lupus nephritis with activity and chronicity indices of four and zero, respectively. A thyroid biopsy showed papillary thyroid carcinoma with a BRAF (V600E) gene mutation.
The patient was diagnosed with SLE and papillary thyroid carcinoma and treated with high-dose prednisone, IV Ig, hydroxychloroquine, and radiofrequency ablation. Her temperature normalized, and gradual remission of SLE occurred. One month later, human Brucella IgG, herpes simplex virus IgM, toxoplasma IgM, CMV IgM, and EBV IgM turned negative without antiviral or antibiotic therapy.
Literature Review
A review of the literature identified four peer-reviewed articles reporting 12 cases of SLE following HPV vaccination. The patients received the bivalent HPV vaccine (HPV2) (1 patient), the quadrivalent HPV vaccine (HPV4) (6 patients), and the HPV9 vaccine (2 patients); the vaccine type was not recorded for three patients. Symptoms appeared after the first vaccination in five patients. A 32-year-old patient was diagnosed with SLE after her third vaccination, and a 19-year-old patient experienced an SLE flare after her second injection, although both had symptoms after their first immunization.
The time from vaccination to symptom onset ranged from 5 days to 4 months. The median onset of symptoms after HPV9 immunization was 5.5 days, shorter than that observed with HPV2 or HPV4 vaccines. Nine patients had a medical or family history of autoimmune disease. Ten patients achieved remission after treatment, while two died.
Clinical Characteristics
Of the 12 patients reviewed, eight presented with a rash (seven with malar rash) and arthralgia/arthritis, seven with fever, fatigue/weakness, alopecia, and renal lesions, four with neurological symptoms, three with oral ulcers and photosensitivity, two with serositis, and one with intestinal pseudo-obstruction. Other symptoms included livedo reticularis, lymphadenopathy, myalgia, and weight loss.
Laboratory Findings
Laboratory studies showed 11 patients with positive ANA, nine with positive anti-dsDNA antibodies, three with positive antiphospholipid antibodies, three with positive anti-Smith antibodies, 10 with hypocomplementemia, nine with elevated ESR, seven with leukopenia/lymphopenia, six with anemia, four with elevated CRP, three with thrombocytopenia, and two with a positive direct Coombs test.
Discussion
SLE is a chronic autoimmune disease triggered by genetic, hormonal, immunologic, and environmental factors. HPV infection may induce or accelerate SLE through immune cross-reaction due to molecular homology. Overlapping peptides between HPV vaccine and human proteins have been identified, suggesting a potential mechanism for autoimmune reactions. Aluminum oxyhydroxide (alum), a common adjuvant in HPV vaccines, has been associated with various autoimmune phenomena. In the reviewed cases, 75% of patients had a medical or family history of autoimmune disease, indicating a genetic predisposition.
The two cases presented here had a shorter median time from vaccination to symptom onset compared to previous studies. This may be due to differences in HPV vaccine types or the higher amounts of virus-like particles and adjuvants in HPV9, which could activate the immune system more rapidly. Both patients had positive serology for various bacterial and viral antibodies, which turned negative in one patient after achieving remission without antiviral or antibiotic therapy. This suggests that the HPV vaccine may trigger an overactivation of B lymphocytes in genetically predisposed individuals, leading to the production of cross-reactive antibodies that cause false-positive serology results. Autoantibodies, however, persist due to the abundance of self-antigens and the transformation of some B lymphocytes into long-lived plasma cells.
Studies indicate that HPV vaccines are highly immunogenic and safe for SLE patients. However, autoimmune phenomena can occur post-vaccination. The incidence rate of SLE among unvaccinated and vaccinated girls was found to be 3.42 and 3.23 per 100,000 person-years, respectively. This suggests that the HPV vaccine may cause earlier onset of SLE in susceptible individuals but not in the general population. It is crucial to evaluate the medical and family history of autoimmune disease and detect autoantibodies before vaccination to prevent serious adverse events.
HPV9 offers protection against nearly 90% of cervical cancers but may stimulate the immune system more strongly than HPV2 or HPV4 vaccines. Recipients of HPV9 are more likely to experience adverse events, necessitating further research to evaluate its safety.
Conclusion
While HPV vaccines are effective in preventing HPV-related diseases, they may trigger SLE in individuals with a genetic predisposition to autoimmune disease. The two cases presented here highlight the potential for severe adverse events following HPV9 vaccination, including the development of SLE and associated complications. It is essential to assess the risk of autoimmune disease before vaccination and monitor patients closely for adverse reactions. Further research is needed to better understand the mechanisms underlying vaccine-induced autoimmune phenomena and to ensure the safety of HPV vaccines, particularly HPV9.
doi.org/10.1097/CM9.0000000000001897
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