CPC- CLINICOPATHOLOGICAL CONFERENCE REPORT
A Rare Case of Massive Gastrointestinal Bleeding as a Cause of Death in a Young Adult with Catastrophic Granulomatosis Polyangiitis
Corresponding Author: Uma N Saikia, Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, Phone: +91 9876288554, e-mail: email@example.com
How to cite this article: Saikia UN, Dhanasekaran V, Sharma S, et al. A Rare Case of Massive Gastrointestinal Bleeding as a Cause of Death in a Young Adult with Catastrophic Granulomatosis Polyangiitis. J Postgrad Med Edu Res 2023;57(3):147–152.
Source of support: Nil
Conflict of interest: None
Patient consent statement: The author(s) have obtained written informed consent from the patient for publication of the case report details and related images.
CLINICAL HISTORY (DR SHEFALI SHARMA)
A 26-year-old male initially presented with a clinical history of cough, fever, headache, and ear fullness with tinnitus in July 2022. The symptoms later progressed to epistaxis and hemoptysis accompanied by swelling of feet in August 2022. In addition, the serum creatinine levels were elevated to 2.07 mg/dL (normal range 0.7–1.3 mg/dL) with red blood cell casts in urine. This prompted antineutrophilic cytoplasmic antibody (ANCA) testing, which revealed positive cytoplasmic ANCA (C-ANCA) positivity. The patient was referred to clinical rheumatology and was started on steroids and intravenous immunoglobulins (Ig). He showed some improvement and was discharged with oral prednisolone, mycophenolate mofetil, and warfarin (10 mg).
In September 2022, his clinical course worsened, and he developed abdominal pain with vomiting and elevated serum creatinine up to 7.1 mg/dL. A renal biopsy was performed, which showed pauci-immune glomerulonephritis. Hemodialysis was initiated, and the patient started on pulse methylprednisolone and intravenous cyclophosphamide.
A diagnosis of granulomatosis polyangiitis (GPA) was considered with sinonasal, lung, and renal involvement, and the patient was initiated with intravenous methylprednisolone, intravenous Igs and mycophenolate mofetil. Despite being on immunosuppressants, the patient’s disease progressed. In October 2022, there was a marked derangement of renal parameters with elevated serum creatinine levels of 7.1 mg/dL, necessitating intravenous cyclophosphamide therapy.
In January 2023, he developed abdominal pain, vomiting, hemoptysis, and loose stools, which were managed conservatively. A noncontrast computed topography of the abdomen did not show any significant findings. The patient’s C-ANCA levels were continuously seen to be in the higher range, and the patient was continued on immunosuppressants.
COURSE AND MANAGEMENT
On 9th January 2023, the patient presented again with abdominal pain and vomiting. The abdominal pain was diffuse and intermittent and relieved with proton pump inhibitors. The vomitus was nonbilious, nonprojectile, and nonbloody. In addition, the patient also had a single episode of hemoptysis and three episodes of loose stools continuously for 6 days.
On 21st January 2023, the patient developed a massive gastrointestinal (GI) bleed for which gastrosurgery was advised after conservative approach and stabilization of the patient. The patient further deteriorated with the development of deranged coagulation parameters, pancytopenia, and development of metabolic acidosis and was shifted to intensive care management. The chest X-ray examination at this point time revealed bilateral effusions in pleural cavities and asymmetric lung shadows. A possibility of lower respiratory tract infection and a diffuse alveolar hemorrhage was considered. Hence the antibiotics were upstaged to colistin with the initiation of hemodialysis, and the patient was intubated due to respiratory distress. From 29th January, the patient was continuously febrile with persistent chest shadows, for which the antibiotics were changed into polymyxin and the additional antifungal. The patient continued to have a fever and developed shock causing cardiopulmonary arrest on 6th February 2023 and the demise of the patient.
The patient was conscious and afebrile, with stable vitals with an oxygen saturation of 96 in the room. There was bilateral nasal crusting. However, no features of cyanosis, elevated jugular venous pressure (JVP), clubbing, icterus, and lymphadenopathy were noted.
Pulse rate: 80/minute regular, respiratory rate: 18/minute, blood pressure: 110/70 mm Hg, and Glasgow Coma Scale: E4V5M6.
Respiratory system: Normal vesicular breath sounds.
Cardiovascular system: S1 and S2 heard, and there is no elevated JVP.
Abdomen: Soft—no mass lesions and tenderness.
Central nervous system: Conscious, oriented, and no focal neurological deficits.
Complete blood count: Marked pancytopenia.
Serum creatinine: 7.1 mg%.
Procalcitonin: 54 ng/mL (normal levels: >0.1/ng/mL).
C-reactive protein: 982 mg/dL (normal levels: >0.3/mg/mL).
Pro–b-type natriuretic peptide: 288 pg/dL (normal levels: >100 pg/mL).
Endotracheal aspirate cultures: Pseudomonas aeruginosa.
Blood cultures: Klebsiella pneumoniae.
Bronchoalveolar lavage fluid cultures: Serratia marcescens.
Cytomegalovirus IgM serology: Negative.
Hepatitis B virus (HBV) IgM antibody: Positive.
HBV DNA: Negative.
Urine examination:Protein: 3+ with RBC casts.
A fine needle aspiration cytology (FNAC) from the right upper zone consolidated area of the lung showed granulomatous inflammation. The special stains for acid-fast bacilli were negative for the Ziehl–Neelson stain, and the Gene Xpert performed on the same material was also negative for tubercular bacilli. However, in view of granulomas, the patient was started on antitubercular therapy.
RADIOLOGICAL EXAMINATION (DR SREEDHARA B CHALUVASHETTY)
A computed tomography (CT) pulmonary angiogram revealed bilateral segmental pulmonary thromboembolism in September 2023.
On 9th January 2022, CT revealed well-defined consolidation with air bronchograms in the right upper lobe with a small wedge-shaped infarct in the left lower lobe of the lung. There was no significant lymphadenopathy, ground glass opacities, or centrilobular nodules noted. The CT abdomen performed at this time revealed an atrophic spleen with symmetrical thickening of the cecum and ascending colon with submucosal edema.
A serial chest X-ray examination in January 2023 revealed bilateral pleural effusion, which showed resolution over the course of the stay. Toward the terminal events, the patient developed lung opacities.
This 26-year-old gentleman presented with constitutional symptoms of headache and fever with nasal crusting and pulmonary involvement in the form of hemoptysis. The FNAC diagnosis of granulomatous inflammation was suggested, following which he was started empirically on antituberculosis therapy with no improvement. He also had pulmonary thromboembolism, and warfarin was started for the same. A differential diagnosis of granulomatosis with polyangiitis with tuberculosis was considered. However, in view of sino-nasal involvement, pulmonary nodule, and renal biopsy showing pauci-immune glomerulonephritis with proteinase 3 (PR-3) positive serology and negative acid-fast bacilli and Gene Xpert studies, a diagnosis of granulomatosis with polyangiitis was favored.
THE FINAL CLINICAL DIAGNOSIS OFFERED
Granulomatosis polyangiitis (GPA) (PR-3 positive with sinonasal, lung and renal involvement).
Diffuse alveolar hemorrhage.
Ischemia of the GI tract.
THE CAUSE OF DEATH WAS REFRACTORY SEPTIC SHOCK
Dr Sanjay Jain: The patient was diagnosed as GPA with respiratory and renal involvement and was receiving immunosuppressants. On 21st January, the patient had a massive GI bleed, which could possibly be from the GI involvement of GPA. At this stage, the patient developed thrombocytopenia which could either be due to sepsis or due to a possible macrophage activation syndrome (MAS). The patient doesn’t have hepatosplenomegaly, and the association of MAS with vasculitis is very uncommon. Now I invite comments from the house.
Dr Aman Sharma: The patient definitively had GPA; there is no doubt in the diagnosis. However, the oddities in these patients are persistent abdominal pain, aggressive course of the disease and late initiation of therapy. The patient terminally developed infections which resulted in sepsis which also added to the poor prognosis of this patient.
Dr Sanjay Jain: This patient had a diffuse pulmonary hemorrhage and GI tract (GIT) hemorrhage together, which are an unusual feature
Dr Anupam: These vascular lesions were not picked by the CT angiogram because of the intermittent nature of the hemorrhage; the cause of the ulcers, whether it is due to vasculitis or infections, cannot be differentiated during endoscopy. A biopsy is required for the differentiation of the same.
Dr Shreedhar: As GPA involves small arteries and capillaries, a CT angiogram cannot pick the active lesions in GPA. As this patient also had a history of pulmonary thromboembolism treated with warfarin, such patients tend to develop bronchial hypertrophy, which can also lead to diffuse alveolar hemorrhage.
Dr Shefali Sharma: The diagnosis of GPA is not in doubt; however, what caused the GI bleed, and infection of GI involvement by GPA is not clear.
Dr Sanjay Jain: We are sure that the patient had GPA though the cause of the GI bleed will only be known after autopsy findings. Dr Uma Nahar, please show us the autopsy findings and reveal the mystery.
AUTOPSY FINDINGS (DR UMA NAHAR SAIKIA)
Good morning, everyone. Indeed, the patient had GPA; however, it was refractory to treatment and catastrophic in spite of adequate treatment leading to complications and the demise of the patient.
A complete autopsy was performed on this patient. Prosectors at the time of the autopsy noticed 1 L of straw-colored fluid in the peritoneal cavity. The pleural and pericardial cavities did not reveal any excess fluid.
Lungs: Both lungs weighed 1600 gm, heavy double the normal weight and diffusely firm to feel. The pleura of both lungs were thickened with the presence of pleural tags (Fig. 1A). On the cut section, the upper lobes of both lungs were consolidated, whereas the lower lungs showed diffuse hemorrhagic areas (Fig. 1B). The upper lobes showed numerous small cavitary nodular lesions coalescing to form large lesions with central areas of necrosis adjacent to the segmental bronchi causing bronchial destruction and centered around pulmonary vessels (Fig. 1B). The periphery of these lesions appeared brownish, with adjacent lung parenchyma showing consolidation.
Microscopic examination showed thickened pleura due to deposition of fibrin admixed with mixed inflammatory cells and fibrosis with vascular proliferation resulting in fibrinous pleuritis. The underlying lung parenchyma showed multiple nodular necrotising lesions of variable size, which were vasculocentric and bronchocentric with central areas of necrosis bordered by dense inflammatory infiltrate with predominant population of neutrophils and nuclear debris admixed with fibrin (Fig. 1C). The inflammation at the periphery of these lesions comprised of lymphocytes, plasma cells with very few multinucleated giant cells destroying the muscular and cartilage layers of bronchial wall with ulceration of bronchial epithelium. Occasional blood vessels near the nodular lesions showed fibrinoid necrosis of the wall with transmural extensive neutrophilic debris and luminal occlusion. The adjacent alveoli show features of capillaritis with neutrophilic infiltration and red blood cell extravasation along with intra-alveolar fibrin deposition (Fig. 1D). Focally, the large arteries and venules showed features of necrotizing vasculitis with endothelial lifting, fibrin deposition, and deposition of myxoid material beneath the internal elastic lamina (Fig.1E). However, no well-formed granulomas were seen in any of the microscopic sections though occasional multinucleated giant cells were seen in the wall of larger veins (Fig.1G). In addition, chronic lesions were also noted in the vessels in the form of fibrosis, hyalinization, subendothelial edema, and narrowing of the lumen. Recanalized thrombi accompanied by reduplication and disruption of the internal elastic lamina was highlighted by elastic Van Gieson stain around cavitary lesions suggesting vascular involvement (Fig.1F). Furthermore, hemosiderin-laden macrophages were seen in sections from the brownish discolored area around these lesions. The immunofluorescence performed for IgG, IgA, and complement component (C3) were negative in the lung tissue.
The microscopy of hemorrhagic consolidated areas in both lungs showed confluent bronchopneumonia having mixed inflammatory infiltrates rich in neutrophils with focal organization, causing obliteration of the bronchial lumen. The adjacent lung revealed alveolar hemorrhage. The Gram Twort highlighted gram-negative cocci within these areas. Focally alveoli showed exuberant type 2 pneumocyte hyperplasia with diffuse alveolar damage by the presence of eosinophilic material deposition lang alveolar wall highlighted on Periodic acid-Schiff’s (PAS) stain (Fig. 1H).
Kidneys: Both weighed 370 gm. The renal arteries were patent without narrowing of the lumen and thrombosis macroscopically. Grossly, both kidneys were swollen with mottling on the external surface, and no petechial lesions were seen (Figs 2A and B). The cut surface shows distinct corticomedullary differentiation; no focal lesions were seen. On microscopy, glomeruli were crowded due to tubular loss and interstitial fibrosis secondary to ischemia caused by the vasculitic process (Fig. 2C). Almost all the glomeruli showed varying ages of crescents (Fig. 2C), including cellular to fibrocellular and fibrous crescents, with underlying tufts demonstrating basement membrane thickening and wrinkling with a break in the Bowman’s capsule highlighted on PAS stain (Fig. 2D). There were no necrotizing lesions, no fibrin thrombi noted within the glomeruli and no granulomas or giant cells were seen. The interlobular small vessels show recanalization thrombi with endothelial swelling accompanied by edema (Figs 2E and F). The tubules show hyaline casts and focal calcification. The arcuate vessels and branches of the main renal artery did not show any active vasculitis or thrombosis. Immunofluorescence on renal tissue was negative for IgG, IgA, and IgM. However, focal 2+ granular deposits of C3 were seen along the capillaries.
The adrenals show features of shock information of lipid depletion and no vasculitis.
Liver: The liver weighed 1600 gm, mildly enlarged with smooth outer and cut surface showed exaggerated mottling (Fig. 2G). There were no nodules and thrombosis of the portal veins. The microscopic examination of the liver shows preserved lobular architecture; there is no evidence of active or healed vasculitis. There was mild sinusoidal congestion in the centrizonal areas (Fig. 2H). The pancreas was grossly unremarkable. The pancreatic and peri-pancreatic blood vessels also do not show active or healed vasculitis.
Spleen: The spleen was shrunken and weighed 80 gm. The cut surface reveals multiple infarcts with scarring leading to prominent crenulations of its borders (Fig. 3A). The microscopy of the spleen reveals thickened capsule with a peripheral old infarct bordered by hyalinization and hemosiderin-laden macrophages (Fig.3B). The hilar and parenchymal blood vessels showed recanalized thrombus with luminal narrowing (Fig.3C). There were no features of active vasculitis in these blood vessels.
Grossly, the small intestine, ileocecal valve, and ascending colon show multiple hemorrhagic lesions surrounded by a blood clot, which were more prominent in the ascending colon (Fig. 3D). These lesions were very firm with ulcerated overlying mucosa (Fig. 3E). The microscopy of these lesions shows linear ulceration of the mucosa covered with fibrin-rich exudates, bacterial colonies, and pauci-cellular inflammatory infiltrate (Figs 3F and G). The underlying capillaries show fresh fibrin thrombi. The adjacent nonulcerated mucosa shows extensive mucosal and submucosal hemorrhage with fibrin thrombi in the capillaries (Fig. 3H). The submucosal vessels showed luminal occlusion due to fibro intimal hyperplasia. The esophagus and stomach also show similar morphological findings (Fig. 3H). The mesenteric and celiac blood vessels do not show features of active or healed vasculitis.
The microscopy from both testes showed features of healed vasculitis in testicular blood vessels along with thickening of the basement membrane of seminiferous tubules due to ischemia (Fig. 4).
Heart: The heart weighed 310 gm. The right inflow and outflow tracts were normal, except for right ventricular thickening, which measured 6 mL. The left inflow and outflow tract show subendocardial hemorrhages (Fig. 4A). Grossly, coronaries do not display any luminal narrowing or thrombosis. Microscopy of the left marginal artery shows intimal proliferation and subendothelial edema with perivascular inflammation extending into the vessel wall (Fig. 4B). The adjacent myocardium shows interstitial edema and no myocardial injury. Similar morphological findings were also observed in the pericardial blood vessels (Fig. 4C). However, sections from the left ventricle, coronary and mural blood vessels do not show any features of vasculitis (Figs 4G and E).
Lymph nodes and bone marrow show features of hemophagocytosis.
FINAL AUTOPSY DIAGNOSIS (PM31256)
Granulomatosis polyangiitis (GPA) with systemic involvement (acute to subacute phase):
Lungs: necrotizing cavitary lesions with healing phase of vasculitis.
Kidneys: Pauci-immune crescentic glomerulonephritis.
Large gut and esophagus: Ischemic ulcers.
Bilateral testicular atrophy.
Heart: Marginal artery involvement.
Necrotizing lobar pneumoniae (gram-negative cocci) with diffuse alveolar damage.
Disseminated intravascular coagulation: Brain, kidneys, and heart.
Secondary hemophagocytosis-Hilar lymph nodes and bone marrow.
Prof Sanjay Jain: Despite adequate immunosuppression, we are seeing both disease activity and infection in this patient.
Dr Aman Sharma: The involvement of the GI tract is a poor prognostic factor. Immunosuppression needs to be initiated as soon as possible to control the disease progression.
Dr Shefali Sharma: GI involvement is not very commonly seen in GPA patients, and if present, it usually has high mortality; also, it could be secondary to therapy.
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