Granulomatosis with polyangiitis complicated by diffuse alveolar hemorrhage, splenic infarction and stroke

Granulomatosis with polyangiitis (GPA) has traditionally been considered a “small to medium vessel” disease, with a preference for renal and pulmonary sites. Patients typically present with fever, cough, dyspnea, hemoptysis, low-grade proteinuria, and hematuria. It can also cause serious complications such as diffuse alveolar hemorrhage (DAH), splenic infarction, and stroke. It is therefore important to recognize these manifestations and make an appropriate diagnosis at an early stage.

A 47-year-old man presented to the emergency department complaining of shortness of breath on exertion, hemoptysis for two weeks, and weight loss of 20 pounds over the past three months, accompanied by loss of appetite. His medical history was unremarkable and he denied a family history of cancer or rheumatologic disorders. However, his social history was notable for past cigarette smoking, marijuana use, and chronic alcohol use. The vital signs tachycardia with a blood pressure of 120/84 and a pulse of 119/min as well as tachypnea with an oxygen saturation of 95% at the nasal cannula were significant. Physical examination was positive for bilateral temporal muscle wasting and oral ulcers (Fig 1), bilateral rales on pulmonary examination, and a purplish rash in the sacral region (Fig 2).

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2: Hyperpigmented rash in the sacral area (black arrowhead).

Laboratory studies were significant for normocytic anemia, leukocytosis, and elevated inflammatory markers (Table 1). Urinalysis was positive for microscopic hematuria and proteinuria. In addition, the patient had three negative sputum samples of acid-fast bacilli to rule out tuberculosis. Antinuclear antibody (ANA), HIV and COVID-19 polymerase chain reaction (PCR) tests were also negative.

Chest x-ray showed extensive bilateral interstitial opacities and bilateral basal nodules. Chest CT angiography was performed on day 1 (Fig 3) and showed extensive bilateral airspace opacities, ground glass, and interstitial opacities that were most prominent in the upper lobes bilaterally. In addition, CT showed nodules within the bases of the lungs, most prominently in the left base of the lungs, measuring up to 5 cm. A contrast-enhanced abdominal CT scan was performed to investigate the reason for the weight loss and revealed splenic and bilateral renal infarctions (Figure 4).

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3: Extensive scattered bilateral airspace opacities confirmed DAH on bronchoscopy.

DAH: diffuse alveolar hemorrhage.

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4: Bilateral renal infarcts (black arrowhead) and extensive splenic infarction (transparent arrowhead) in CT abdomen.

The patient was diagnosed with presumably community-acquired pneumonia and started on doxycycline and ceftriaxone. However, the next day the patient’s hypoxia worsened. A rheumatologic etiology was suspected. Laboratories were positive for rheumatoid factor (RF), anti-CCP, and anti-Pr3 and negative for anti-dsDNA, anti-MPO, anti-SSA, and anti-SSB (Table 1). We made a diagnosis of GPA based on the positive anti-Pr3 antibody. The patient proceeded with bronchoscopy and bronchoalveolar lavage, which showed DAH. Cytology showed reactive respiratory cells and hemosiderin-laden macrophages against a background of inflammatory cells and fibrin, consistent with inflammatory pneumonitis. The patient responded well to methylprednisolone 1 g for three days followed by rituximab 375 mg/m2 weekly. A repeat CT scan on day 8 of hospitalization showed improved pulmonary nodal opacities (Fig 5). He was then discharged and followed up by the rheumatologist. The patient was readmitted approximately 40 days after discharge for a major thrombotic stroke of the right middle cerebral artery. He was treated with tissue plasminogen activator and thrombectomy and discharged home stabilized after 10 days. There were no respiratory symptoms, abdominal pain, fever, joint pain, or rash.

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5: CT chest on day 8, improved nodule formation is noted.

GPA can be complicated by renal infarction [1-3], and patients with active disease show altered coagulation and fibrinolysis indices. This leads to a hypercoagulable state that increases venous thromboembolic risk, which is no different between MPO and PR3 vasculitis [4]. Such prothrombotic complications can be observed in patients who have previously achieved remission after immunosuppressive therapy [5]. DAH is also a recognized life-threatening complication of ANCA-associated vasculitis (AAV). It can present with a triad of hemoptysis, pulmonary infiltrates, and anemia [6]. In a retrospective review, it was found that one-third (8/24) of patients with DAH had AAV [7]. In various studies, the incidence of DAH in AAV is between 8% and 36% [8-10].

Stroke is another complication of GPA. In a retrospective study, the incidence of developing ischemic stroke after 10 years is 11%, four times higher than in the general population [11]. Accelerated atherosclerosis has been an emerging pathogenic complication of AAV in recent years. Studies have shown that increased cytokine production, particularly T-helper-17 and T-helper-1, and lipid accumulation leading to arterial inflammation are associated with atherosclerosis [12,13]. Increased intima-media thickness of the carotid artery is also a reason for ischemic stroke in AAV patients [14]. Studies have shown that administration of immunosuppressants and statins was beneficial in primary stroke prevention [15]. Nevertheless, no protective effect of platelet aggregation inhibitors (aspirin, clopidogrel) was found in this study. However, this study was limited to patients in Korea and more research is needed on stroke prevention in AAV patients.

Splenic infarction is an underestimated manifestation of AAV. The spleen is predisposed to infarction due to occlusive infarction of the distal splenic arteries and arterioles and terminal vessels without collaterals [16]. Clinically apparent splenic infarction appears to be a rarer phenomenon, with few reported cases, but typically presents with left-sided abdominal pain. The patient in this case report had no abdominal symptoms, but contrast-enhanced CT abdomen showed a splenic infarction. It is not a common finding in AAV in the literature, but it is most likely found in patients with GPA. It can be asymptomatic and likely to be underestimated, but when present it can help distinguish microscopic polyangiitis from other AAVs. Although the prevalence and specificity of splenic infarction in GPA have not been established, existing articles indicate that splenic infarction is indicative of GPA. One study found that spleen pathologies were observed in 19 patients (28%), seven of whom (37%) had splenic infarction [17]. There are few cases reporting splenic infarction in patients with microscopic polyangiitis (MPA) and eosinophilic GPA [18,19]. Because splenic infarction occurs almost exclusively in PR3-ANCA positive vasculitis, this helps clinicians differentiate between MPA and GPA. Therefore, physicians should consider GPA in patients with splenic infarction suspected of having vasculitis [20]. Splenic infarction should also not be ignored in GPA patients, as it has been shown that patients can have major infarction or auto-splenectomy. Therefore, clinicians should consider vaccination against preventable infections, including Neisseria, Streptococcus pneumoniae, Haemophilus, etc. In this case, abdominal CT was performed prior to diagnosis of GPA, but splenic infarction should not be overlooked when a patient is diagnosed with GPA becomes. An abdominal CT scan to rule out spleen involvement would be beneficial.

GPA is a multisystem small vessel vasculitis. It poses a diagnostic challenge as its various symptoms and manifestations can mimic other diseases such as infection or malignancy. Recognizing the presentation of GPA promptly is critical, as prompt induction of immunosuppression with high-dose steroids, rituximab, or cyclophosphamide is important for a more favorable chance of remission and a reduction in mortality. DAH is a life-threatening complication in patients with GPA that can be detected by imaging. Prompt identification of GPA as the etiology of DAH can lead to earlier treatment initiation and improved remission rates. The risk of stroke increases in patients with GPA, and treatment with immunosuppressants (glucocorticoids, cyclophosphamide, rituximab, azathioprine/mizoribine, and methotrexate) and statins can reduce the risk. Splenic infarction should be considered in GPA patients, and splenic imaging should be performed in this patient population to avoid misdiagnosis. Splenic and renal infarction may be associated with increased morbidity and mortality in this patient population and more data are needed to assess these risks.