A Case of Destructive Wegener's Granulomatosis Complicated by Cytomegalovirus Infection

Peer M. Aries; Sebastian Ullrich; Wolfgang L. Gross Authors and Disclosures Posted: 10/05/2006; Nat Clin Pract Rheumatol. 2006;2(9):511-515. 2006 Nature Publishing Group
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Summary & the Case Discussion of Diagnosis Discussion of Treatment Options Conclusion
References

Summary & the Case

Summary

Background: A 63-year-old man with a 4-year history of Wegener's granulomatosis presented with hemoptysis, palatal ulceration and sensorimotor polyneuropathy. Investigations: Physical examination, serologic testing, proteinase 3 enzyme-linked immunosorbent assay, IgG and IgM specific to Epstein-Barr virus enzyme-linked immunosorbent assay, MRI of the middle face, an ear, nose and throat consultation, immunohistochemical staining of an esophageal sample obtained from esophagogastroduodenoscopy, polymerase chain reaction of cytomegalovirus (CMV) DNA from esophageal and blood samples, and measurement of pp65 early antigen. Diagnosis: Wegener's granulomatosis with progressive palatal ulceration and osseous destruction complicated by CMV-related esophagitis during induction treatment. Management: Induction treatment with cyclophosphamide pulse therapy was discontinued and antiviral therapy with ganciclovir was started. Cyclophosphamide pulse therapy was later reintroduced, but there was subsequent CMV reactivation, and, therefore, cyclophosphamide pulse therapy was suspended again and ganciclovir and intravenous immunoglobulin were started. After control of CMV, cyclophosphamide pulse therapy was reinitiated. Prolonged immunosuppressive therapy controlled disease activity, without CMV reactivation.
The Case

A 63-year-old male patient with a 4-year history of Wegener's granulomatosis (WG) presented with pulmonary infiltrates and hemoptysis, nasal crusting with bloody discharge, inflammatory sensorimotor polyneuropathy and palatal mucosal ulcerations causing painful food ingestion. A physical examination was performed. Laboratory and serologic testing revealed a nonspecific elevation of the acute phase reactants. Antineutrophil cytoplasmic antibody (ANCA) test results were positive and revealed a cytoplasmic fluorescence pattern. Antigen specificity to proteinase 3 (PR3) was verified by PR3 enzyme-linked immunosorbent assay. Enzyme-linked immunosorbent assays for IgG and IgM antibodies specific to Epstein-Barr virus (EBV) were negative. An interdisciplinary diagnostic work-up, including MRI and an ear, nose and throat consultation, showed massive granulomatous lesions of the sinuses, and pulmonary infiltrates, but excluded further organ involvement, as well as infections and malignancies. A diagnosis of generalized WG was made on the basis of the criteria of the American College of Rheumatology. Treatment with cyclophosphamide pulse therapy 15 mg/kg every 20 days, in combination with an equivalent dosage of intravenous mesna for uroprotection, plus glucocorticoids (prednisolone 2 mg/kg per day), was implemented. The patient's pulmonary and neurologic symptoms were almost completely ameliorated in the course of treatment, but his low-grade palatal ulceration persisted. The patient was switched after 10 months to maintenance therapy with azathioprine 2 mg/kg per day; however, 12 weeks later he presented with a severe, painful palatal ulceration with initiation of osseous destruction and pulmonary infiltrates. Cyclophosphamide pulse therapy 15 mg/kg every 20 days was reintroduced, but had to be discontinued after two pulses because of cytomegalovirus (CMV) infection. Infection was confirmed by positive immunohistochemical staining of an esophageal sample obtained from esophagogastroduodenoscopy and by DNA amplification via qualitative polymerase chain reaction (PCR). A test for pp65 early antigen was negative at this time. The patient also had neutropenia (CD4+ T-cell count 286/l (normal count 400-1450/l)) and massive ulcerative hemorrhagic esophagitis leading to anemia (haemoglobin 80 g/l (normal value 140-180 g/l)). After CMV was successfully treated with 5 mg/kg ganciclovir twice a day for almost 2 weeks, and persistent active replication of CMV was excluded by PCR, ganciclovir treatment was stopped. Cyclophosphamide pulse therapy 15 mg/kg every 20 days was retried 15 days after discontinuation of antiviral therapy, but had to be suspended after the first pulse because of CMV reactivation. Reactivation of CMV was confirmed by a positive PCR result from an esophageal specimen, and by the observation of clinical symptoms similar to those experienced previously. A test for pp65 early antigen was negative. Ganciclovir 5 mg/kg twice a day for 21 days was reintroduced, in combination with intravenous immunoglobulin (IVIG) 30 g per day for 5 days for the control of vasculitis disease activity.

Despite IVIG treatment, WG disease activity increased, resulting in destructive palatal inflammation with complete penetration of the osseous palate (Figure 1). The patient suffered severe complications, particularly with food ingestion. In addition, the patient developed sensorimotor pareses in both legs, with almost complete immobilization. Reintroduction of ganciclovir 5 mg/kg twice a day for 21 days successfully treated CMV infection. Fourteen days after discontinuation of antiviral therapy, immunosuppressive therapy with cyclophosphamide pulse therapy 15 mg/kg every 20 days regained control of WG disease activity after nine pulses. In the future, plastic surgery might be recommended to repair the palatal destruction, if WG remains in remission.

Figure 1. Wegener's granulomatosis with ear, nose and throat involvement and palatal destruction.
(Enlarge Image)

Discussion of Diagnosis
Wegener's Granulomatosis
In the presented case, diagnosis of WG fulfilled the 1990 criteria of the American College of Rheumatology,[1] and was also in accordance with the nomenclature of the Chapel Hill Consensus Conference.[2] Although histologic proof of either necrotizing small-vessel vasculitis, pauci immune glomerulonephritis or characteristic granulomatous inflammation is desirable, WG can be diagnosed by typical clinical symptoms, evidence of PR3-specific ANCAs and other parameters of granulomatous inflammation and vasculitis, including granulomatous masses viewed by imaging, hematuria or hemoptysis. In this case, biopsy was refused by the patient, with the exception of endoscopic procedures; therefore, we relied on nonhistologic criteria for the diagnosis of WG. According to the European Vasculitis Study Group, which defined different disease stages of WG, this patient had generalized WG; this diagnosis was made on the basis of the patient's systemic vasculitis, which threatened vital organ function.[3] Granulomatous inflammation of the upper respiratory tract is present in almost all patients with WG, but ulcerations of the palate, tongue or gingiva are rare and distinct manifestations.[4,5] Initially, inflammation is most often restricted to the mucosa, as can be seen in Figure 2, but it can be destructive and go on to affect the adjacent osseous structures, if therapy is inadequate (Figure 1). An important differential diagnosis for destructive midfacial changes is lethal midline granuloma-an extranodal mature peripheral T-cell and natural-killer-cell lymphoma. Lethal midline granuloma can be associated with EBV infection. In contrast to WG, lethal midline granuloma rarely involves the lower respiratory tract or the peripheral nervous system, and it is not associated with cytoplasmic ANCAs. As a result of the involvement of the lower respiratory tract and peripheral nervous system

in this patient, the detection of cytoplasmic ANCAs, and negative test results for EBV infection, WG was considered to be the most likely diagnosis.

Figure 2. Wegener's granulomatosis with ear, nose and throat manifestations and beginning mucosal ulcerations.
(Enlarge Image)

Cytomegalovirus Infection
Active CMV infection made the treatment of WG in this patient challenging. CMV infection, defined as asymptomatic circulating virus, can be detected in the early stages (before the development of characteristic cytopathic effects) by PCR of CMV DNA and by measuring pp65 early-antigen expression in peripheral leukocytes; however, it should be noted that CMV tissue infection can occur without evidence of early-antigen expression. IgM and IgG antibodies specific to CMV were not measured in our patient, because they provide only indirect evidence of recent CMV infection and can persist for several months; therefore, they can provide misleading information in cases of CMV reactivation. In the presented patient, CMV disease was confirmed initially by immunohistochemical staining and PCR of CMV DNA from an esophageal specimen. It remains speculative whether the negative PCR result after the first antiviral course was misleading, and whether persistent replication remained undetected. At the time of CMV reactivation, test results for pp65 early antigen were consistently negative, but repeated esophageal biopsies and PCR showed positive qualitative results for CMV DNA. CMV infection and reinfection can cause laboratory abnormalities, including absolute lymphocytosis. Leukopenia with lymphopenia is not unusual during induction treatment with cyclophosphamide pulse therapy, and might necessitate an adjustment to the dosage. Bone-marrow suppression caused by alkylating therapies normally recovers within days after discontinuation of the alkylating agent. If leukopenia persists, CMV infection has to be excluded as its cause. Interestingly, leukopenia related to either CMV infection or cyclophosphamide pulse therapy does not usually halt the disease activity of vasculitis. A differential-diagnostic challenge in this case was caused by hemorrhagic esophagitis. Ulcerative CMV-related esophagitis has been reported in patients with malignancies or acquired immunodeficiency syndrome, and after transplantation,[6] but it is rarely reported in other circumstances.[7] Esophageal involvement in systemic vasculitides is extremely rare and almost exclusive to Behet's disease. Active vasculitis in this patient initially indicated a vasculitic manifestation in the gastrointestinal tract, but this cause was ruled out after a positive CMV immunohistochemical stain and PCR of CMV DNA from several esophageal specimens.

As we have demonstrated, differentiating between viral infection and complications of treatment can be difficult, but is particularly important when deciding further treatment options.

Discussion of Treatment Options

Standard treatment for ANCA-associated vasculitis is still cyclophosphamide pulse therapy 2 mg/kg and glucocorticoids, at an initial dose of 1 mg/kg.[8] Cyclophosphamide pulse therapy is now preferably used for a period of 3-6 months, depending on the persisting disease activity. Long-term cyclophosphamide pulse therapy and high-dose glucocorticoids have been shown to be less preferable because of therapy-related toxicity. Recently, the European Vasculitis Study Group published their pooled data of 386 patients with ANCA-associated vasculitis and revealed that cyclophosphamide therapy and leukopenia are major risk factors for severe infections.[9] Infections are the main cause of death in patients with vasculitis, besides vasculitis itself; therefore, treatment-related leukopenia and infections deserve special attention in the treatment of ANCAassociated vasculitides. In any case, therapy for vasculitis has to be appropriate to the present situation and, if necessary, abandoned. In the case patient, CMV disease with leukopenia and esophagitis forced us to discontinue induction therapy with cyclophosphamide pulse therapy, despite very active WG. Ulcerative palatal destruction and sensorimotor polyneuropathy developed further during that time, but all immunosuppressive therapy had been contraindicated. IVIG could be justified for treating treatment-refractory WG patients, particularly if leukopenia caused by inductiontherapy limits further immunosuppression;[10] however, it was not sufficient to completely control disease activity in this patient. Rituximab might also be an adequate therapy in this situation, but so far, a lack of data regarding rituximab in this setting, and frustrating results from similar granulomatous courses of WG,[11] led to the decision not to use this treatment. The Centers for Disease Control and Prevention[12] and Hodson et al.[13] have recommended that ganciclovir should be administered to hematopoetic-stem-cell-transplant recipients and solid-organ recipients already at risk for CMV disease (i.e. all CMV-seropositive recipients) until 100 days after transplantation; however, no such official recommendation has been published for patients with autoimmune diseases treated with immunosuppressive therapy. In practice, ganciclovir is widely used in patients with proven CMV infection. Complicating, hematologic suppression, in particular neutropenia, seems to be a common adverse event in ganciclovir therapy; however, ganciclovir therapy is recommended unless the absolute neutrophil count falls below 500/l.[14] For CMV gastrointestinal-tract disease, ganciclovir and foscarnet are the two established treatment options. Although both therapies seem to be equally effective,[15] ganciclovir is recommended as firstline therapy because it is cheaper, more convenient, and is associated with less renal toxicity than is foscarnet. The exact duration of therapy required for treatment of CMV gastrointestinal disease is not yet clear; some reports recommend a 2-week course, and others a 6-week course.[16,17] For patients who fail to respond to initial anti-CMV therapy, or who relapse during antiviral therapy, there are several treatment options, including switching to an alternative agent (ganciclovir or foscarnet), combining gancliclovir and foscarnet, or introducing cidofovir.[18] Whether maintenance therapy is needed after resolution of CMV gastrointestinal disease remains controversial.

Discussion of Treatment Options

Standard treatment for ANCA-associated vasculitis is still cyclophosphamide pulse therapy 2 mg/kg and glucocorticoids, at an initial dose of 1 mg/kg.[8] Cyclophosphamide pulse therapy is now preferably used for a period of 3-6 months, depending on the persisting disease activity. Long-term cyclophosphamide pulse therapy and high-dose glucocorticoids have been shown to be less preferable because of therapy-related toxicity. Recently, the European Vasculitis Study Group published their pooled data of 386 patients with ANCAassociated vasculitis and revealed that cyclophosphamide therapy and leukopenia are major risk factors for severe infections.[9] Infections are the main cause of death in patients with vasculitis, besides vasculitis itself; therefore, treatment-related leukopenia and infections deserve special attention in the treatment of ANCA-associated vasculitides. In any case, therapy for vasculitis has to be appropriate to the present situation and, if necessary, abandoned. In the case patient, CMV disease with leukopenia and esophagitis forced us to discontinue induction therapy with cyclophosphamide pulse therapy, despite very active WG. Ulcerative palatal destruction and sensorimotor polyneuropathy developed further during that time, but all immunosuppressive therapy had been contraindicated. IVIG could be justified for treating treatment-refractory WG patients, particularly if leukopenia caused by induction-therapy limits further immunosuppression;[10] however, it was not sufficient to completely control disease activity in this patient. Rituximab might also be an adequate therapy in this situation, but so far, a lack of data regarding rituximab in this setting, and frustrating results from similar granulomatous courses of WG,[11] led to the decision not to use this treatment. The Centers for Disease Control and Prevention[12] and Hodson et al.[13] have recommended that ganciclovir should be administered to hematopoetic-stem-cell-transplant recipients and solid-organ recipients already at risk for CMV disease (i.e. all CMV-seropositive recipients) until 100 days after transplantation; however, no such official recommendation has been published for patients with autoimmune diseases treated with immunosuppressive therapy. In practice, ganciclovir is widely used in patients with proven CMV infection. Complicating, hematologic suppression, in particular neutropenia, seems to be a common adverse event in ganciclovir therapy; however, ganciclovir therapy is recommended unless the absolute neutrophil count falls below 500/l.[14] For CMV gastrointestinal-tract disease, ganciclovir and foscarnet are the two established treatment options. Although both therapies seem to be equally effective, [15] ganciclovir is recommended as first-line therapy because it is cheaper, more convenient, and is associated with less renal toxicity than is foscarnet. The exact duration of therapy required for treatment of CMV gastrointestinal disease is not yet clear; some reports recommend a 2week course, and others a 6-week course.[16,17] For patients who fail to respond to initial anti-

CMV therapy, or who relapse during antiviral therapy, there are several treatment options, including switching to an alternative agent (ganciclovir or foscarnet), combining gancliclovir and foscarnet, or introducing cidofovir.[18] Whether maintenance therapy is needed after resolution of CMV gastrointestinal disease remains controversial.