IgG4-associated multifocal systemic fibrosis presenting with fever of unknown origin
Sir,Autoimmune pancreatitis is characterized by significant lymphoplasmacytic infiltration and fibrosis of the pancreas,1 with high serum IgG4 concentrations and/or IgG4-positive plasma cell infiltration.2,3 The disease may be complicated by a variety of extra-pancreatic lesions,2,3 suggesting the possibility of systemic disease, recently described as IgG4-associated multifocal systemic fibrosis.4
Of 31 patients admitted to our hospital with a fever of unknown origin (FUO) from 1 October 1997 to 31 July 2005, 10 did not receive a definite diagnosis during their admission.5 Three of these 10 had evidence of IgG4-associated multifocal systemic fibrosis.
Patient 1 was a 71-year-old man, admitted with a high fever, anorexia, lower back pain and polydipsia. Physical examination showed remittent fever and bilateral swelling of the submandibular gland. Investigation revealed panhypopituitarism and diabetes insipidus. Serum IgG4 and soluble IL-2 receptor (sIL2r) levels were elevated. Imaging studies showed hypophysitis, sialadenitis and retroperitoneal fibrosis, but no pancreatic lesions. Histology of biopsies of the submandibular gland and retroperitoneal fibrosis showed IgG4-positive plasma cell infiltration (Figure 1, a and b). All symptoms improved after corticosteroid treatment.
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Patient 2 was a 67-year-old man, admitted with a high fever. Physical examinations showed remittent fever, fine crackles on chest auscultation and hepatomegaly. Serum IgG4 and sIL2r levels were elevated. Imaging studies showed interstitial pneumonia, but no pancreatic lesions. Transbronchial lung biopsy showed thickening of the interstitial septa in the alveoli with infiltration of the IgG4-positive plasma cells (Figure 1, c and d). Liver biopsy specimens showed diffuse granulomatous lesions, unlike those typical of sarcoidosis or autoimmune hepatitis. He responded favourably to corticosteroids.
Patient 3 was a 37-year-old man, admitted with a high fever and general fatigue. Physical examinations showed remittent fever and tenderness of the neck without lymphadenopathy. Later, he complained of muscle pain and paraesthesia of the lower extremities and of vertigo. Serum IgG4 and collagen disease-related data were within normal ranges. Chest computed tomography and Ga-67 scintigram showed a soft mass in the right lung, and a biopsy specimen showed IgG4-positive plasma cell infiltration (Figure 1, e and f), indicating a pseudotumour composed of plasma cell granulomas. Imaging studies showed no pancreatic lesions. All clinical symptoms improved after the administration of corticosteroids.
The symptoms of these three patients (high serum IgG4 concentration, prominent IgG4-bearing plasma cell infiltration into various organs regardless of the pancreatic involvement, and a favourable response to corticosteroid therapy) correspond with those suggested for IgG4-associated multifocal systemic fibrosis.4
The serological characteristics are high serum levels of IgG4 and sIL2r. Levels of sIL2r are also increased in Wegener's granulomatosis and Churg-Strauss syndrome, which are sometimes causes of FUO. However, interleukin-1ß, interleukin-6 and tumour necrosis factor-
were all within the normal range. There was no obvious mechanism for the rising fever in these three patients.
Our experience suggests that it may be useful to measure serum IgG4 in cases of fever where the diagnosis is unclear.
First Department of Internal Medicine
Center for Health, Safety and Environmental Management
Second Department of Internal Medicine
Shinshu University School of Medicine
Matsumoto City
Japan
email: tsushima{at}hsp.md.shinshu-u.ac.jp
References
1. Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. (1995) Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci 40 1561–8.[CrossRef][Web of Science][Medline]
2. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K. (2001) High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344 732–8.
3. Kawaguchi K, Koike M, Tsuruta K, Okamoto A, Tabata I, Fujita N. (1991) Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol 22 387–95.[CrossRef][Web of Science][Medline]
4. Van der Vliet HJ and Perenboom RM. (2004) Multiple pseudotumors in IgG4-associated multifocal systemic fibrosis. Ann Intern Med 141 896–7.
5. Mourad O, Palda V, Detsky AS. (2003) A Comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med 163 545–51.
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