Rare Genetic Autoimmune Disease COPA Syndrome Diagnosed After 17-Year Diagnostic Odyssey

A rare genetic autoimmune disorder known as COPA syndrome has claimed the life of a 45-year-old man whose disease evaded a definitive diagnosis for nearly two decades, according to a detailed case report published in Respirology Case Reports. The account, compiled by clinicians working across multiple specialties in Brazil, traces an extraordinary medical journey that began in 2006 with a near-fatal bout of respiratory failure and ended in 2026 with a fatal septic complication that arose during immunosuppressive therapy. The case offers a sobering illustration of how difficult it remains to recognize rare monogenic immune disorders in adults, and of the delicate balance clinicians must strike between suppressing dangerous inflammation and leaving patients vulnerable to life-threatening infection.

COPA syndrome is caused by mutations in the COPA gene, which encodes the alpha subunit of the coatomer protein complex, a cellular machine responsible for shuttling proteins between the endoplasmic reticulum and the Golgi apparatus. When this trafficking system breaks down, proteins accumulate abnormally within cells, triggering cellular stress and activating the type I interferon pathway, a central alarm system of innate immunity. The result is profound immune dysregulation characterized by the production of autoantibodies and chronic inflammation that primarily targets the lungs, kidneys and joints. The condition is usually inherited in an autosomal dominant pattern, although sporadic cases without any family history occur, and the classic clinical triad comprises interstitial lung disease or diffuse alveolar hemorrhage, arthritis and kidney disease.

The patient at the center of the report first fell ill at the age of 27, when he developed flu-like symptoms, coughing up blood and acute respiratory failure severe enough to require orotracheal intubation and eighteen days of mechanical ventilation. Chest computed tomography at that time revealed diffuse alveolar damage and a nonspecific interstitial pneumonia pattern. Within the same year he began showing signs of renal dysfunction, and a year later he suffered a second episode of acute respiratory failure. Given the striking combination of lung bleeding and kidney injury, his physicians initially suspected a pulmonary–renal syndrome such as ANCA-associated vasculitis or Goodpasture syndrome, and in 2008 he was started on an intensive course of twelve cycles of the immunosuppressant cyclophosphamide.

That treatment achieved partial stabilization, but it could not halt the underlying disease. Serial chest CT scans over the following years documented progressive fibrotic damage to the lungs, including upper lobe–predominant honeycombing, increasing reticulation, traction bronchiectasis and persistent ground-glass opacities. By 2022, high-resolution imaging showed established fibrotic remodeling alongside findings suggesting active inflammatory lung injury, a coexistence of chronic scarring and recurrent acute damage that is characteristic of the heterogeneous pulmonary manifestations of COPA syndrome. A transbronchial biopsy yielded inadequate tissue, so the surgical team proceeded to an open lung biopsy. The histopathology proved remarkably rich: prominent lymphoid follicles consistent with follicular bronchiolitis, a non-fibrotic nonspecific interstitial pneumonia pattern with marked interstitial edema, patches of organizing pneumonia containing intra-alveolar fibrin in an acute fibrinous and organizing pneumonia pattern, fibrin thrombi within airspaces, and evidence of both recent and remote alveolar hemorrhage in the form of hemosiderin-laden macrophages.

The kidneys told a parallel story. A renal biopsy performed in November 2008 demonstrated focal proliferative and necrotizing glomerulonephritis with early crescent formation in six of nine glomeruli examined, confirming active immune-mediated renal injury. Immunofluorescence showed no linear deposition of immunoglobulin along the glomerular basement membrane, which definitively excluded Goodpasture syndrome. Serologic testing during reevaluation between 2021 and 2022 revealed a positive antinuclear antibody test at a titer of 1:320 in a homogeneous pattern and a positive p-ANCA at 1:80, but antibodies directed against myeloperoxidase, proteinase 3, double-stranded DNA, Smith, ribonucleoprotein, Ro/SSA and La/SSB were all negative. Kidney function was impaired, with a creatinine clearance of 60 mL per minute and 24-hour proteinuria of 907.5 mg. The atypical ANCA positivity, the authors note, reflects the immune dysregulation inherent to COPA syndrome rather than primary ANCA-associated vasculitis, a distinction with major consequences for classification and treatment.

The definitive answer arrived only in January 2024, when next-generation sequencing identified a heterozygous COPA variant, NM_004371.4:c.698G>A (p.Arg233His), classified as likely pathogenic under American College of Medical Genetics criteria. This variant had been reported previously in individuals with COPA syndrome and is associated with pulmonary and autoimmune manifestations, and its identification finally unified the patient’s pulmonary hemorrhage, crescentic glomerulonephritis and arthralgia under a single genetic diagnosis. Notably, the patient had denied any family history of autoimmune, interstitial lung or renal disease, and genetic testing of relatives was unavailable, underscoring how sporadic presentations can escape suspicion for years. Pulmonary function testing in 2022 revealed a mixed moderate obstructive and restrictive ventilatory defect, with a forced vital capacity of 53 percent predicted, a forced expiratory volume in one second of 44 percent predicted and a markedly reduced diffusing capacity for carbon monoxide at 42 percent predicted. A six-minute walk test showed oxygen saturation falling from 96 percent to 85 percent after only 285 meters.

Once the diagnosis was confirmed, the nephrology team initiated maintenance immunosuppression with methotrexate 10 mg weekly and prednisone 10 mg daily, and the patient remained clinically stable and asymptomatic for roughly a year. The course then deteriorated for reasons that were tragically behavioral as much as biological. The patient self-adjusted his medications, discontinued methotrexate without medical advice because he attributed his symptoms to a viral infection, and stopped attending scheduled follow-up visits. After approximately a year without immunosuppressive therapy, he returned with worsening renal function and significant proteinuria while his lung disease remained stable. Suspecting immune-mediated renal relapse, clinicians began pulse cyclophosphamide at 1 g daily for three consecutive days together with pulse methylprednisolone at the same dose and schedule, with no documented neutropenia during treatment.

Shortly after that single cycle, the patient developed acute diverticulitis complicated by sepsis from a perforated diverticulum, an event for which he had no prior history of diverticular disease. He underwent an emergency Hartmann’s procedure with end colostomy for surgical source control, but despite emergency abdominal surgery and prolonged broad-spectrum antibiotics, he progressed to septic shock and multiorgan failure and died. The case authors emphasize that severe infection during potent immunosuppression is among the principal causes of mortality reported in COPA syndrome, alongside progressive respiratory failure and end-stage kidney disease, and that patients receiving cyclophosphamide and similar agents require particularly vigilant multidisciplinary monitoring.

Beyond its clinical drama, the report carries broader lessons for the field. Because COPA syndrome is rare and phenotypically variable, diagnostic delay is common, especially when adult presentations overlap with far more prevalent autoimmune and interstitial lung diseases. The authors argue that the diagnosis should be suspected in patients with diffuse alveolar hemorrhage, unexplained pulmonary–renal syndromes, follicular bronchiolitis or interstitial lung disease beginning in childhood or early adulthood, particularly when autoantibodies are positive without a definitive connective tissue disease diagnosis. Genetic testing, they contend, should be pursued whenever diagnostic uncertainty persists despite multidisciplinary evaluation. On the therapeutic horizon, Janus kinase inhibitors such as baricitinib and ruxolitinib, which target the type I interferon pathway at the root of the disease, have shown promise in case reports and small studies and may prove especially valuable for severe or refractory disease. The authors call for multicenter studies and international registries to standardize treatment strategies and define the natural history of the condition, and they conclude that early recognition, sustained treatment adherence and careful monitoring during immunosuppressive therapy are essential to prevent relapse and fatal complications in this rare but devastating disorder.

Subject of Research: COPA syndrome, a rare autosomal dominant genetic autoimmune disorder affecting the lungs, kidneys and joints

Article Title: A Rare Case of COPA Syndrome: Multisystem Relapse and Fatal Septic Complication

Article References: Castro Velasco Fernandes, F., Torres, P. P. T. E. S., de Paula Silveira‐Lacerda, E., Rabahi, M., Velasco Magalhaes Fernandes, L., Lopes, L. R., Moreira, M. A. R., & Rabahi, M. F. (2026). A Rare Case of COPA Syndrome: Multisystem Relapse and Fatal Septic Complication. Respirology Case Reports, 14(9), Article e70742. https://doi.org/10.1002/rcr2.70742

Image Credits: AI Generated

DOI: 10.1002/rcr2.70742

Keywords: COPA syndrome, genetic autoimmune disease, interstitial lung disease, diffuse alveolar hemorrhage, glomerulonephritis, COPA gene mutation, immunosuppression, sepsis, next-generation sequencing, type I interferon, follicular bronchiolitis, pulmonary-renal syndrome