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Whipple’s disease: acquired resistance to trimethoprim-sulfamethoxazole
2390
Letters to the Editor
AJG – Vol. 95, No. 9, 2000
Figure 1. (A) Family pedigree of the patient with a Muir-Torre syndrome. Carriers are indicated by MUT⫹. Age of onset and cancer side are reported inside figures; the age at the present time and age of death are reported outside figures. CRC ⫽ colorectal cancer; UC ⫽ urological cancer; SC ⫽ skin cancer; GC ⫽ gastric cancer; OL ⫽ oligodendroglioma. (B) DGGE homozygosity and heterozygosity patterns of normal DNA 308 and DNA of patients 303 and 304. The arrow in the electropherogram indicates the heterozygous germline 2239 del AT in exon 14, codon 747 of the hMSH2 gene.
REFERENCES 1. Cohen PR, Kohn SR, Kuzrock R. Association of sebaceous gland tumours and internal malignancy: The Muir-Torre syndrome. Am J Med 1991;90:606 –13. 2. Kolodner RD, Hall NR, Lipford J, et al. Structure of the human hMSH2 locus and analysis of two Muir-Torre syndrome kindreds for hMSH2 mutations. Genomics 1994;24:516 –26. 3. Kruse R, Lamberti C, Wang Y, et al. Is the mismatch repair deficient type of Muir-Torre syndrome confined to mutations in the hMSH2 gene? Hum Genet 1996;98:747–50. 4. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87:159 –70. 5. De la Hoya M, Diaz-Rubio E, Calde´s T. Denaturing gradient gel electrophoresis-based analysis of loss of heterozygosity distinguishes nonobvious, deleterious BRCA1 variants from nonpathogenic polymorphisms. Clin Chem 1999;45:2028 –30. 6. Lerman C, Hughes C, Trock BJ, et al. Genetic testing in families with hereditary nonpolyposis colon cancer. JAMA 1999;17:1618 –22. 7. Kruse R, Rutten A, Lamberti C, et al. Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutation similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria. Am J Hum Genet 1998;63: 63–70. 8. Vasen H, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996;110:1020 –7. 9. Lynch HT, Lynch PM, Pester J, et al. The cancer family syndrome: Rare cutaneous phenotypic linkage of Torre’s syndrome. Arch Intern Med 1981;141:607–11.
Reprint requests and correspondence: Trinidad Calde´s, Ph.D., Laboratory of Molecular Oncology, San Carlos University Hospital (Pab. B) c/Martin Lagos s/n, 28040 Madrid, Spain. Received Mar. 8, 2000; accepted Apr. 25, 2000.
Whipple’s Disease: Acquired Resistance to Trimethoprim-Sulfamethoxazole TO THE EDITOR: We report the case of a 56-yr-old woman who was admitted to the hospital with fever, abdominal pain, loss of appetite, asthenia, and weight loss. Physical examination was normal. Laboratory tests showed hyperleukocytosis (12 ⫻ 109/L) and an elevated erythrocyte sedimentation rate (ESR) of 55 mm/h. Abdominal CT scan showed celiac, hepatic vascular axis, and mesenteric lymphadenopathies. Mesenteric adenopathies were biopsied during laparotomy. The biopsy specimens showed numerous aggregates of foamy macrophages containing granular periodic acid-Schiff (PAS)–positive material. Upper endoscopy was normal but duodenal and gastric specimens showed the same features as the mesenteric adenopathies. Whipple’s disease was diagnosed. Cerebral CT and echocardiography were normal. The patient was treated with oral trimethoprim-sulfamethoxazole (TMP-SMX) (160 mg/800
AJG – September, 2000
mg) twice a day for 1 yr. Symptoms improved within a few days and biological values returned to normal. Duodenal and gastric specimens taken 6 and 12 months after treatment initiation showed persistent infiltration by PAS-positive macrophages, but the intraabdominal lymphadenopathies had decreased in size and number on repeat CT. TMP-SMX was withdrawn after 1 yr. One month later, the patient presented with loss of appetite, weight loss, and biological signs of inflammation. TMP-SMX was resumed at the same dose as previously for 4 months, and the patient recovered rapidly. Symptoms and biological abnormalities again recurred on drug withdrawal. Despite further treatment with the same TMP-SMX regimen the symptoms worsened. Duodenal biopsies again showed infiltration by PAS-positive macrophages. Polymerase chain reaction (PCR) tests, using primers specific for the 16S rRNA gene of Tropheryma whippelii were positive on duodenal and gastric specimens but negative on peripheral blood. We concluded that the disease had relapsed and become resistant to TMP-SMX, and prescribed oral penicillin (Oracillin), 500,000 IU four times a day. The patient improved after 2 wk. After 1 yr of this therapy, the abdominal CT scan was normal, gastric biopsy specimens were normal, and duodenal biopsy specimens contained very few PASpositive macrophages. PCR tests of duodenal and gastric tissues and peripheral blood were negative. After 2 yr on the same treatment, the patient was still asymptomatic and PCR tests remained negative. Whipple’s disease is a systemic bacterial infection and the causative agent is Tropheryma whippelii, recently identified (1). Various empirical antibiotic regimens have been tested in this setting, such as tetracycline, TMP-SMX, cephalosporins, and penicillin. The optimal treatment period is poorly documented, but ⱖ1 yr is usually recommended. TMP-SMX has been found to induce complete clinical remission (2). We obtained a good initial response to TMPSMX therapy, followed by a relapse after drug discontinuation. The symptoms again responded to a second course of the same antibiotic, but a second relapse failed to respond to TMP-SMX. This, to our knowledge, is the first reported occurrence of acquired resistance to TMP-SMX. However, PCR has proved useful in diagnosing the disease and in monitoring bacterial eradication during antibiotic therapy (3). The positive amplification of duodenal and gastric samples during the third relapse indicated that the patient was still infected by Tropheryma whippelii despite TMP-SMX treatment, whereas the signal disappeared on oral penicillin. These negative PCR results on biopsy specimens were in keeping with the improvement in clinical manifestations and histological findings, which showed almost complete clearance of PAS-positive macrophage infiltration. This sequence of events suggests that repeated TMP-SMX treatment led to acquisition of resistance. PCR also has good predictive value for clinical relapse, with a negative predictive value of 100% when PCR results are negative (4). These findings raise the question of whether negative PCR
Letters to the Editor
2391
results safely warrant treatment withdrawal. Long-term follow-up of treated patients is required to answer this question. The fact that the bacillus has been recently cultivated (5) provides hope for the possibility of testing antibiotic susceptibilities. Finally, this observation shows that oral penicillin is an effective, well tolerated alternative for chronic treatment of Whipple’s disease after failure of TMP-SMX. Michae¨l Le´vy, M.D. Claire Poyart, M.D., Ph.D. Dominique Lamarque, M.D. Jean-Charles Delchier, M.D. Service d’He´patologie et de Gastroente´rologie Hoˆpital Henri Mondor Cre´teil, France Service de Bacte´riologie, Virologie, Parasitologie, Hygie`ne Hoˆpital Necker-Enfants-Malades Paris, France
REFERENCES 1. Relman DA, Schmidt TM, MacDermott RP, et al. Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 1992;327:293–301. 2. Feurle GE, Marth T. An evaluation of antimicrobial treatment for Whipple’s disease. Tetracycline versus trimetoprim-sulfamethoxazole. Dig Dis Sci 1994;39:1642– 8. 3. Pron B, Poyart C, Abachin E, et al. Diagnosis and follow-up of Whipple’s disease by amplification of the 16S rRNA gene of Tropheryma whippelii. Eur J Clin Microbiol Infect Dis 1999; 18:62–5. 4. Ramzan NN, Loftus Jr E, Burgart LJ, et al. Diagnosis and monitoring of Whipple disease by polymerase chian reaction. Ann Intern Med 1997;126:520 –7. 5. Raoult D, Birg ML, La Scola B, et al. Cultivation of the bacillus of Whipple’s Disease. N Engl J Med 2000;342:620 –5. Reprint requests and correspondence: Michae¨l Le´vy, M.D., Service d’He´patologie et de Gastroente´rologie, Hoˆpital Henri Mondor, 51 avenue du Mare´chal de Lattre de Tassigny, 94000, Cre´teil, France. Received Mar. 1, 2000; accepted Apr. 25, 2000.
Autoimmune Pancreatitis and Hepatitis: An Uncommon Association TO THE EDITOR: We report a 44-yr-old patient with autoimmune hepatitis type 1, who developed high serum levels of pancreatic enzymes and enlargement of the pancreas on CT scan, whose ERCP let to see a normal biliary tree, without stones or obstructions and, an irregular narrowing in the distal main pancreatic duct. A dramatic response to corticosteroid therapy was observed and a possible autoimmune origin of pancreatitis is speculated. The association of autoimmune hepatitis and pancreatitis seems to be very uncommon and this diagnosis must be considered
Letters to the Editor
AJG – Vol. 95, No. 9, 2000
Figure 1. (A) Family pedigree of the patient with a Muir-Torre syndrome. Carriers are indicated by MUT⫹. Age of onset and cancer side are reported inside figures; the age at the present time and age of death are reported outside figures. CRC ⫽ colorectal cancer; UC ⫽ urological cancer; SC ⫽ skin cancer; GC ⫽ gastric cancer; OL ⫽ oligodendroglioma. (B) DGGE homozygosity and heterozygosity patterns of normal DNA 308 and DNA of patients 303 and 304. The arrow in the electropherogram indicates the heterozygous germline 2239 del AT in exon 14, codon 747 of the hMSH2 gene.
REFERENCES 1. Cohen PR, Kohn SR, Kuzrock R. Association of sebaceous gland tumours and internal malignancy: The Muir-Torre syndrome. Am J Med 1991;90:606 –13. 2. Kolodner RD, Hall NR, Lipford J, et al. Structure of the human hMSH2 locus and analysis of two Muir-Torre syndrome kindreds for hMSH2 mutations. Genomics 1994;24:516 –26. 3. Kruse R, Lamberti C, Wang Y, et al. Is the mismatch repair deficient type of Muir-Torre syndrome confined to mutations in the hMSH2 gene? Hum Genet 1996;98:747–50. 4. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87:159 –70. 5. De la Hoya M, Diaz-Rubio E, Calde´s T. Denaturing gradient gel electrophoresis-based analysis of loss of heterozygosity distinguishes nonobvious, deleterious BRCA1 variants from nonpathogenic polymorphisms. Clin Chem 1999;45:2028 –30. 6. Lerman C, Hughes C, Trock BJ, et al. Genetic testing in families with hereditary nonpolyposis colon cancer. JAMA 1999;17:1618 –22. 7. Kruse R, Rutten A, Lamberti C, et al. Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutation similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria. Am J Hum Genet 1998;63: 63–70. 8. Vasen H, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996;110:1020 –7. 9. Lynch HT, Lynch PM, Pester J, et al. The cancer family syndrome: Rare cutaneous phenotypic linkage of Torre’s syndrome. Arch Intern Med 1981;141:607–11.
Reprint requests and correspondence: Trinidad Calde´s, Ph.D., Laboratory of Molecular Oncology, San Carlos University Hospital (Pab. B) c/Martin Lagos s/n, 28040 Madrid, Spain. Received Mar. 8, 2000; accepted Apr. 25, 2000.
Whipple’s Disease: Acquired Resistance to Trimethoprim-Sulfamethoxazole TO THE EDITOR: We report the case of a 56-yr-old woman who was admitted to the hospital with fever, abdominal pain, loss of appetite, asthenia, and weight loss. Physical examination was normal. Laboratory tests showed hyperleukocytosis (12 ⫻ 109/L) and an elevated erythrocyte sedimentation rate (ESR) of 55 mm/h. Abdominal CT scan showed celiac, hepatic vascular axis, and mesenteric lymphadenopathies. Mesenteric adenopathies were biopsied during laparotomy. The biopsy specimens showed numerous aggregates of foamy macrophages containing granular periodic acid-Schiff (PAS)–positive material. Upper endoscopy was normal but duodenal and gastric specimens showed the same features as the mesenteric adenopathies. Whipple’s disease was diagnosed. Cerebral CT and echocardiography were normal. The patient was treated with oral trimethoprim-sulfamethoxazole (TMP-SMX) (160 mg/800
AJG – September, 2000
mg) twice a day for 1 yr. Symptoms improved within a few days and biological values returned to normal. Duodenal and gastric specimens taken 6 and 12 months after treatment initiation showed persistent infiltration by PAS-positive macrophages, but the intraabdominal lymphadenopathies had decreased in size and number on repeat CT. TMP-SMX was withdrawn after 1 yr. One month later, the patient presented with loss of appetite, weight loss, and biological signs of inflammation. TMP-SMX was resumed at the same dose as previously for 4 months, and the patient recovered rapidly. Symptoms and biological abnormalities again recurred on drug withdrawal. Despite further treatment with the same TMP-SMX regimen the symptoms worsened. Duodenal biopsies again showed infiltration by PAS-positive macrophages. Polymerase chain reaction (PCR) tests, using primers specific for the 16S rRNA gene of Tropheryma whippelii were positive on duodenal and gastric specimens but negative on peripheral blood. We concluded that the disease had relapsed and become resistant to TMP-SMX, and prescribed oral penicillin (Oracillin), 500,000 IU four times a day. The patient improved after 2 wk. After 1 yr of this therapy, the abdominal CT scan was normal, gastric biopsy specimens were normal, and duodenal biopsy specimens contained very few PASpositive macrophages. PCR tests of duodenal and gastric tissues and peripheral blood were negative. After 2 yr on the same treatment, the patient was still asymptomatic and PCR tests remained negative. Whipple’s disease is a systemic bacterial infection and the causative agent is Tropheryma whippelii, recently identified (1). Various empirical antibiotic regimens have been tested in this setting, such as tetracycline, TMP-SMX, cephalosporins, and penicillin. The optimal treatment period is poorly documented, but ⱖ1 yr is usually recommended. TMP-SMX has been found to induce complete clinical remission (2). We obtained a good initial response to TMPSMX therapy, followed by a relapse after drug discontinuation. The symptoms again responded to a second course of the same antibiotic, but a second relapse failed to respond to TMP-SMX. This, to our knowledge, is the first reported occurrence of acquired resistance to TMP-SMX. However, PCR has proved useful in diagnosing the disease and in monitoring bacterial eradication during antibiotic therapy (3). The positive amplification of duodenal and gastric samples during the third relapse indicated that the patient was still infected by Tropheryma whippelii despite TMP-SMX treatment, whereas the signal disappeared on oral penicillin. These negative PCR results on biopsy specimens were in keeping with the improvement in clinical manifestations and histological findings, which showed almost complete clearance of PAS-positive macrophage infiltration. This sequence of events suggests that repeated TMP-SMX treatment led to acquisition of resistance. PCR also has good predictive value for clinical relapse, with a negative predictive value of 100% when PCR results are negative (4). These findings raise the question of whether negative PCR
Letters to the Editor
2391
results safely warrant treatment withdrawal. Long-term follow-up of treated patients is required to answer this question. The fact that the bacillus has been recently cultivated (5) provides hope for the possibility of testing antibiotic susceptibilities. Finally, this observation shows that oral penicillin is an effective, well tolerated alternative for chronic treatment of Whipple’s disease after failure of TMP-SMX. Michae¨l Le´vy, M.D. Claire Poyart, M.D., Ph.D. Dominique Lamarque, M.D. Jean-Charles Delchier, M.D. Service d’He´patologie et de Gastroente´rologie Hoˆpital Henri Mondor Cre´teil, France Service de Bacte´riologie, Virologie, Parasitologie, Hygie`ne Hoˆpital Necker-Enfants-Malades Paris, France
REFERENCES 1. Relman DA, Schmidt TM, MacDermott RP, et al. Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 1992;327:293–301. 2. Feurle GE, Marth T. An evaluation of antimicrobial treatment for Whipple’s disease. Tetracycline versus trimetoprim-sulfamethoxazole. Dig Dis Sci 1994;39:1642– 8. 3. Pron B, Poyart C, Abachin E, et al. Diagnosis and follow-up of Whipple’s disease by amplification of the 16S rRNA gene of Tropheryma whippelii. Eur J Clin Microbiol Infect Dis 1999; 18:62–5. 4. Ramzan NN, Loftus Jr E, Burgart LJ, et al. Diagnosis and monitoring of Whipple disease by polymerase chian reaction. Ann Intern Med 1997;126:520 –7. 5. Raoult D, Birg ML, La Scola B, et al. Cultivation of the bacillus of Whipple’s Disease. N Engl J Med 2000;342:620 –5. Reprint requests and correspondence: Michae¨l Le´vy, M.D., Service d’He´patologie et de Gastroente´rologie, Hoˆpital Henri Mondor, 51 avenue du Mare´chal de Lattre de Tassigny, 94000, Cre´teil, France. Received Mar. 1, 2000; accepted Apr. 25, 2000.
Autoimmune Pancreatitis and Hepatitis: An Uncommon Association TO THE EDITOR: We report a 44-yr-old patient with autoimmune hepatitis type 1, who developed high serum levels of pancreatic enzymes and enlargement of the pancreas on CT scan, whose ERCP let to see a normal biliary tree, without stones or obstructions and, an irregular narrowing in the distal main pancreatic duct. A dramatic response to corticosteroid therapy was observed and a possible autoimmune origin of pancreatitis is speculated. The association of autoimmune hepatitis and pancreatitis seems to be very uncommon and this diagnosis must be considered