Case Presentation
A 20-year old Caucasian woman in septic shock with multiorgan dysfunction was transferred to our intensive care unit. Her medical history was remarkable for allergic asthma and Basedow's disease. She had previously undergone a left-sided hemithyroidectomy and right-sided subtotal resection.
About four weeks before admission to the transferring hospital, our patient had been treated with cefuroxime due to a retroareolar inflammation two years after a right-sided breast piercing. Because of the sustained fever and diarrhea, we substituted cefuroxime with metronidazole, suspecting an antibiotic-associated process. Metronidazole was then switched to vancomycin, with the assumption that our patient had pseudomembranous colitis. A colonoscopy showed inflammation and multiple small ulcerations of her entire colon, with the greatest extent in her ileum, cecum and sigma. However, neither pathogen germs nor Clostridium difficile toxin could be detected in stool samples and her blood and urine specimens were also sterile. A wound swab of her increasingly necrotic right breast showed Staphylococcus aureus, Actinomyces turicensis and Peptostreptococcus species. Consequently, the progressively damaged tissue was explored and extensively excised to exclude an abscess. Because of the considerable aggravation of her general condition, the antibiotic treatment was again diversified to a three-fold treatment with imipenem and cilastatin, moxifloxacin, and fluconazole. Owing to her hemodynamic and respiratory insufficiency, our patient was transferred to our intensive care unit.
During admission to our ward, ventilation was conducted with 100% oxygen, and our patient needed high catecholamine doses. She was also anuric, with a creatinine level of 5.0mg/dL (reference range 0.7 to 1.2mg/dL) and elevated liver parameters, with total bilirubin 2.9mg/dL (reference range 0.2 to 1.0mg/dL), aspartate transaminase 2572U/L (reference range 10 to 50U/L) and alanine transaminase 608U/L (reference range 10 to 50U/L). She had leukocytosis, with a white blood cell count of 27.0G/L (reference range 4.3 to 10.0G/L). Her C-reactive protein level was >230mg/L (reference range <5mg/dL) and procalcitonin level was 9.3μg/L (reference range 0.1 to 0.5μg/L). An immediate colonoscopy showed multiple ulcerations of the colonic mucosa (Figure 1).
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Figure 1.
Macroscopic aspect of the colonic mucosa. Multiple small ulcerations of a few millimeter diameter were seen dispersed over the entire mucosa of the colon (arrows).
Because our patient was therapy-refractory and had persisting signs of septic shock and a risk of perforation, a subtotal colectomy was indicated. Just before the beginning of the abdominal surgery, her pulmonary gas exchange worsened. When examined by bronchoscopy, there was no evidence of an obstruction; however, the mucosa of her bronchi was highly inflamed and vulnerable. We observed bleeding originating from her upper airway. The ventilatory conditions were instantly ameliorated by a laparotomy - equivalent to the release of intra-abdominal compartment syndrome. Because of the incipient necrosis of her gall bladder, we performed a subtotal colectomy and a cholecystectomy. During the surgery, 20cm of her rectum were left and blindly closed according to Hartmann's approach, with an ileostomy and a laparostomy.
Postoperatively, we initiated a calculated therapy with meropenem and caspofungin as well as vancomycin to cover a possible translocation of C. difficile or its toxins. Furthermore, continuous veno-venous hemofiltration was started.
Permanent stabilization of our patient's organ functions could not be achieved. Hemodynamic, pulmonary and renal failure still persisted and her liver enzyme levels increased massively (aspartate transaminase 8848U/L, alanine transaminase 1039U/L, total bilirubin 9.4mg/dL), correlating with ischemic necrosis in liver segments six and seven detected by ultrasonic testing. Moreover, our patient showed recurrent ventricular and supraventricular tachycardia culminating in a short-term asystole. Echocardiography did not reveal any pathological changes. All blood, tracheal secretion and abdominal swab samples stayed free of pathological germs. A sudden rise in lactate necessitated a second-look operation, during which we found no evidence of mesenteric ischemia.
Histologic examination of her colon showed multiple superficial areas of microulceration of the mucosa, lamina propria mucosae and, to a lesser extent, the lamina submucosa (Figure 2). Medium-sized arteries and arterioles of her entire colon, appendix and gallbladder showed acute vasculitic changes with fibrinoid necrosis of the walls and diffuse infiltration with neutrophil granulocytes, accompanied by a strong perivascular histiocyte-rich and partially granulomatous reaction (Figure 3A,B). Many arterioles also had intraluminal platelet-rich thrombi (Figure 3A), others were complete obliterated by inflammatory cells. The affected vessels were localized in the submucosal layer of her bowel and in her gall bladder. These findings strongly suggested an autoimmune multisystem disease like Wegener's granulomatosis or microscopic polyangiitis. A diagnosis of Wegener's granulomatosis was confirmed by the results of the serologic antibody tests: her c-ANCA titer was considerably elevated at 1:2560 specific for subclass proteinase 3 (PR3) (>200kU/L). After the histopathological diagnosis and the serological tests, immunosuppression with high doses of corticosteroids and plasmapheresis were started.
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Figure 2.
Histological aspect of one ulcer of the colonic mucosa. Ulceration is restricted to the mucosa and partially to the submucosa. No alteration of the architecture of the colonic crypts or granuloma formation was found. MM: muscularis mucosa; MP: muscularis propria; MU: mucosa, SM: submucosa.
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Figure 3.
A and B: Microscopical aspect of two arterioles with vasculitic changes. (A) Vessels are surrounded by dense histiocytic infiltrates forming, in many cases, granulomas. Many vessels also show platelet-rich thrombi associated to inflammatory changes of the wall. (B) The vascular wall shows large areas of fibrinoid necrosis with neutrophil granulocytes that were nearly complete destroyed. * lumen of the vessel; FN: fibrinoid necrosis; HIS: histiocytic infiltration; IN: intima; SM: smooth muscle; TH: thrombus.
Continuing a dosage of 100mg prednisolone daily and plasmapheresis twice a day for almost a week, we gradually achieved a durable stabilization of our patient's circulation and lung function, a constant downsizing of the ischemic area in her right liver lobe and a cumulative resumption of urine production. After tapering catecholamines and eliminating about 10L of extravascular fluids, it was possible to close the laparostomy and extubate our patient. Her gas exchange was borderline and she required highly intensive airway treatment and intermittent application of continuously positive airway pressure.
A couple of days later, she developed an acute abdomen and we measured a leap in leukocytes up to 75.0G/L. A computed tomography scan showed multiple hypodense areas in her liver appearing as partial necrosis and her spleen failed to show any contrast at all.
A splenectomy was performed due to multiple septic infarctions, although several samples taken from biopsies of the hepatic lesions were sterile.
Postoperatively, our patient could be extubated without difficulty, her leukocyte level fell and after a perioperative deterioration of kidney function, her creatinine and urea levels stayed within an acceptable range because of reparatory polyuria. She did not show any neurological deficits, slowly regained her strength and could be transferred to a standard ward only five days post-splenectomy.
Plasmapheresis was continued three times a week and prednisolone was gradually reduced to 50mg per day. After completion of wound healing, cyclophosphamide treatment could be initiated.
Retrospectively, we discovered some further, interesting aspects about our patient's medical history: when she was diagnosed with Basedow's disease two years before, our patient had positive titers for thyroid peroxidase antibodies (380U/mL; normal range <35U/mL), microsomal antibodies (1:6400; normal range <1:100) and thyroid-stimulating hormone receptor antibodies (29.5U/L; normal range <1U/L). Her parents reported that she had complained about painful knees after exercising and gingival problems for several weeks before exacerbation of the Wegener's disease.