- Email: [email protected]
Strongyloidiasis as a possible cause of nephrotic syndrome
CASE REPORT
Strongyloidiasis as a Possible Cause of Nephrotic Syndrome Yuk-kei Yee, MBBS, Cheuk-sum Lam, MBBS, Chun-yu Yung, MBBS, Tak-lun Que, MBBS, Tze-hoi Kwan, MBBS, Tak-cheung Au, MBBS, and Ming-leung Szeto, MBBS ● Chronic strongyloidiasis is a mild disease and has never been reported to be associated with nephrotic syndrome. Disseminated strongyloidiasis is known to have high mortality, but it frequently is not diagnosed until autopsy. We report a patient with nephrotic syndrome developing disseminated strongyloidiasis after steroid therapy. The findings in renal biopsy, the time course of the development, and resolution of nephrotic syndrome after thiabendazole treatment suggested a possible causal relationship between chronic strongyloidiasis and nephrotic syndrome. The case also demonstrated the importance of early diagnosis in disseminated strongyloidiasis and the good clinical outcome of early treatment before the development of organ failure. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Strongyloides stercoralis; nephrotic syndrome; immunosuppression.
S
TRONGYLOIDIASIS is usually a mild and uncommonly diagnosed problem in developed countries. With the wider application of immunosuppressive therapy, disseminated strongyloidiasis is increasingly encountered. Despite the repeated reporting of fatal cases of disseminated strongyloidiasis, this severe form is frequently neglected. Four cases of disseminated strongyloidiasis have been diagnosed in our hospital in the past few years (not reported) and all of the patients died because of late diagnosis. Chronic strongyloidiasis is usually asymptomatic. Although renal involvement and nephrotic syndrome have been observed in patients with disseminated strongyloidiasis,1 chronic strongyloidiasis has never been reported as a cause of nephrotic syndrome. Here we report a patient with nephrotic syndrome developing disseminated strongyloidiasis after steroid treatment. Not only did he survive but there was resolution of nephrotic syndrome after treatment with thiabendazole. CASE REPORT A 55-year-old cleaning worker presented to our hospital in February 1997 because of progressive ankle swelling for 2 months. He was otherwise asymptomatic and did not have any chest or gastrointestinal symptoms. His past health was good. He did not smoke or drink. Physical examination showed only generalized edema. Further investigations showed features compatible with nephrotic syndrome. Results of initial screening for secondary causes were all negative (Table 1). Renal biopsy showed minor glomerular abnormality with mesangial hypercellularity (Fig 1). Immunofluorescence showed patchy small amounts of granular deposits of immunoglobulin M (IgM) and C3 in glomerular basement membrane. Electron microscopy of one glomerulus showed extensive fusion of the foot processes, mildly
increased mesangial cells and matrix, absence of electrondense deposit, and unremarkable basement membrane. Idiopathic glomerulonephritis was diagnosed. The patient was treated with salt restriction and diuretics. He consulted a private nephrologist, and prednisolone 20 mg twice daily was prescribed. He was admitted 6 weeks later into our hospital again because of epigastric pain, nausea, vomiting, and watery diarrhoea without blood or mucus. Physical examination indicated only edema and abdominal distension. Investigations showed the persistence of hypoalbuminemia, evidences of small bowel dilation in abdominal radiograph, and inflamed duodenum in upper endoscopy. There was raised serum IgE (419 IU/mL), but not eosinophilia. Conservative treatment was instituted initially. Because of the risk of sepsis, prednisolone was decreased to 10 mg daily initially and then tailed off gradually despite the presence of proteinuria and hypoalbuminemia in admission. A course of antibiotic therapy was also given. However, there was persistently high output from the Ryle’s tube. One-week later, duodenal biopsy showed strongyloides infestation (Fig 2). Thiabendazole was prescribed, and the patient’s condition responded promptly with resolution of intestinal obstruction in 1 week. Surprisingly, his nephrotic syndrome remitted after the eradication of strongyloides. There was progressive decrease in proteinuria in the following few months (latest ⫽ 0.29 g/d). Stool for strongyloides remained negative after treatment. One year later, the patient was still asymptomatic and not on any medication. The patient refused to have a second renal biopsy and defaulted further follow-up.
From the Departments of Medicine and Clinical Pathology, Tuen Mun Hospital, Hong Kong. Received December 4, 1998; accepted in revised form February 16, 1999. Address reprint requests to Yuk-kei Yee, MBBS, Department of Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3306-0036$3.00/0
American Journal of Kidney Diseases, Vol 33, No 6 (June), 1999: E4
1
2
YEE ET AL Table 1. Initial Laboratory Finding
Hemoglobin White cell count Platelet count ESR Urea Creatinine Albumin Urinary protein Creatinine clearance Cholesterol C3 C4 Anti-nuclear factor ANCA HbsAg Anti-HCV
14.9 g/dL 9.9 ⫻ 109/L 278 ⫻ 109/L 109 37.0 mg/dL 1.12 mg/dL 1.5 g/dL 9.45 g/d 80 mL/min 561 mg/dL 112 mg/dL* 34 mg/dL* Negative Negative Negative Negative
*Reference ranges of C3 and C4 are 88 to 201 and 16 to 47, respectively.
DISCUSSION
Strongyloides stercoralis is endemic in southeast Asia,2 including southern China. The local incidence is not available, but no case was found when the stool samples of over 80 renal patients were screened for the parasites in our center. The sensitivity of stool examination is just around 30%.3 Examination of multiple stool samples4 or use of enzyme-linked immunosorbent assay test to detect serum antibodies to Strongyloides5,6 improve the sensitivity. History of travel to endemic areas, as with our patient, increases the risk of this parasitic infection.
Strongyloides stercoralis is unique among human helminths in its capability of autoinfection. Humans get infected when the infective filariform larvae penetrate the skin or mucous membranes, usually as a result of contact with contaminated soil.7 The adult female, 2 mm long, usually resides in the mucosa of the upper jejunum. Parasitic males have not been observed. Females reproduce parthenogenetically. Because the level of autoinfection is usually low, chronic strongyloidiasis is usually asymptomatic and commonly not recognized. Disturbed host-parasite balance will accelerate autoinfection, resulting in hyperinfection with or without the presence of parasites outside the gastrointestinal or respiratory tract. Widespread invasion of filariform larvae into various organs, including the lung, liver, kidney, and even central nervous system, may occur. This results in hemorrhage, inflammation, and sepsis. Disseminated strongyloidiasis is diagnosed in this situation. However, hyperinfection syndrome and disseminated strongyloidiasis are commonly used interchangeably. Steroid is the most important cause of hyperinfection.8,9 Other predisposing factors include immunosuppression, acquired immunodeficiency syndrome, renal failure, diabetes mellitus, malnutrition, and achlorhydria.10-12 Because the manifestation is usually nonspecific, diagnosis is not uncommonly delayed, and mortality of disseminated strongyloidiasis is as high as 50% to 80%.2,8,13
Fig 1. Masson’s Trichrome stain of renal biopsy. There are focal mild to moderate mesangial proliferation and increase in matrix; patchy lymphoplasmacytic infiltrate in the stroma is also noted.
STRONGYLOIDES AND NEPHROTIC SYNDROME
3
Fig 2. H&E stain of duodenal biopsy. Duodenum was heavily infiltrated by neutrophils, lymphocytes, and plasma cells. Abundant parasitic worms were found, in both adult and larval forms.
Only early diagnosis and treatment can improve the prognosis. A high level of suspicion is necessary. Glomerular changes have been reported in patients with disseminated strongyloidosis.2 However, glomerulonephritis with nephrotic syndrome has not been reported in patients with chronic strongyloidiasis. In our case, the typical glomerular abnormalities of strongyloidiasis, such as mesangial hypercellularity and granular deposits of IgM and C3 in glomerular basement membrane, were noticed before the occurrence of disseminated strongyloidiasis. The nephrotic syndrome remitted after eradication of strongyloidiasis in this patient. These suggest that Strongyloides may be causally related to the glomerulonephritis. Immunofluorescence staining for parasitic antigens in the renal biopsy specimen is helpful in supporting this hypothesis, but it is not available in our laboratory. Reactive arthritis and uveitis secondary to strongyloides infection also have been reported. Rapid improvement after treatment with wormicide was observed.14 Parasitic glomerulopathies is now an important chapter in nephrology. Glomerulopathies have been noticed in patients with infection by malaria, schistosomiasis, filariasis, kala-azar, trypanosomiasis, toxoplasmosis, and echinococcosis.15 The clinical manifestation varies in different infections, ranging from abnormalities in urinalysis to proteinuria to renal failure. Renal
involvement can occur as a result of secondary amyloidosis or outflow tract obstruction. Nephrotic syndrome as a result of parasitic glomerulopathy has been reported only in malaria, schistosomiasis, filariasis, and cysticercosis.15,16 Immune complexes play a major role in the pathogenesis of these glomerulopathies. Recovery after successful treatment of the parasites have been reported in patients with falciparum malarial nephropathy, Class II schistosomal glomerulopathies, and cysticercosis-related nephrotic syndrome.15,16 In conclusion, Strongyloides may be responsible for the nephrotic syndrome in our patient because of the findings in renal biopsy, the time course of the development, and resolution of nephrotic syndrome after thiabendazole treatment. Nonetheless, reporting of similar cases and animal studies is needed to clarify this causal relationship. Moreover, the possibility of strongyloidiasis should be considered even in nonendemic areas such as Hong Kong, before and after the administration of steroid therapy, so as to prevent death from this potentially fatal disease. REFERENCES 1. Churg J, Bernstein J, Glassock RJ: Renal disease: Classification and Atlas of Glomerular Diseases (ed 2). Tokyo, Japan, Igaku-Shoin, 1995, pp 232-251 2. Cook GC: Strongyloides stercoralis hyperinfection syndrome: How often is it missed? Q J Med 244:625-629, 1987 3. Dreyer G, Fernandes-Silva E, Alves S, Rocha A, Albu-
4
querque R, Addiss D: Patterns of detection of Strongyloides stercoralis in stool specimens: Implications for diagnosis and clinical trials. J Clin Microbiol 34:2569-2571, 1996 4. Sato Y, Kobayashi J, Toma H, Shiroma Y: Efficacy of stool examination for detection of Strongyloides infection. Am J Trop Med Hyg 53:248-250, 1995 5. Neva FA: Biology and immunology of human strongyloidiasis. J Infect Dis 153:397-406, 1986 6. Lindo JF, Conway DJ, Atkins NS, Bianco AE, Robinson RD, Bundy DA: Prospective evaluation of enzymelinked immunosorbent assay and immunoblot methods for the diagnosis of endemic Strongyloides stercoralis infection. Am J Trop Med Hyg 51:175-179, 1994 7. Mahmoud AAF: Strongyloidiasis. CID 23: 949-953, 1996 8. Igra-Siegman Y, Kapila R, Sen P, Kaminski ZC, Louria DB: Syndrome of hyperinfection with Strongyloides stercoralis. Rev Infect Dis 3:397-407, 1981 9. Genta RM: Dysregulation of strongyloidiasis: A new hypothesis. Clin Microbiol Rev 5:345-355, 1992 10. Goannella RA, Broitman ZA, Zamcheck N: Influence
YEE ET AL
of gastric acidity on bacterial and parasitic enteric infections. Ann Intern Med 78:271-276, 1973 11. Hagelskjaer LH: A fatal case of systemic strongyloidiasis and review of the literature. Eur J Clin Microbiol Infect Dis 13:1069-1074, 1994 12. Lessnau KD, Can S, Talavera W: Disseminated Strongyloides stercoralis in human immunodeficiency virusinfected patients. Chest 104:119-122, 1993 13. Genta RM: Global prevalence of strongyloidiasis: Critical review with epidemiologic insights into the prevention of disseminated disease. Rev Infect Dis 11:755-767, 1989 14. Patey O, Bouhali R, Breuil J, Chapuis L, CourillonMallet A, Lafaix C: Arthritis associated with Strongyloides stercoralis. Scand J Infect Dis 22:233-236, 1990 15. Barsoum RS: Parasitic glomerulopathies. Proc R Coll Physicians Edinb 27:283-299, 1997 16. Rabenantoandro R, Rasoloarijaona L, Raharivelina C, et al: Extramembranous glomerulonephritis and cysticercosis. Sante 6:254-257, 1996.
Strongyloidiasis as a Possible Cause of Nephrotic Syndrome Yuk-kei Yee, MBBS, Cheuk-sum Lam, MBBS, Chun-yu Yung, MBBS, Tak-lun Que, MBBS, Tze-hoi Kwan, MBBS, Tak-cheung Au, MBBS, and Ming-leung Szeto, MBBS ● Chronic strongyloidiasis is a mild disease and has never been reported to be associated with nephrotic syndrome. Disseminated strongyloidiasis is known to have high mortality, but it frequently is not diagnosed until autopsy. We report a patient with nephrotic syndrome developing disseminated strongyloidiasis after steroid therapy. The findings in renal biopsy, the time course of the development, and resolution of nephrotic syndrome after thiabendazole treatment suggested a possible causal relationship between chronic strongyloidiasis and nephrotic syndrome. The case also demonstrated the importance of early diagnosis in disseminated strongyloidiasis and the good clinical outcome of early treatment before the development of organ failure. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Strongyloides stercoralis; nephrotic syndrome; immunosuppression.
S
TRONGYLOIDIASIS is usually a mild and uncommonly diagnosed problem in developed countries. With the wider application of immunosuppressive therapy, disseminated strongyloidiasis is increasingly encountered. Despite the repeated reporting of fatal cases of disseminated strongyloidiasis, this severe form is frequently neglected. Four cases of disseminated strongyloidiasis have been diagnosed in our hospital in the past few years (not reported) and all of the patients died because of late diagnosis. Chronic strongyloidiasis is usually asymptomatic. Although renal involvement and nephrotic syndrome have been observed in patients with disseminated strongyloidiasis,1 chronic strongyloidiasis has never been reported as a cause of nephrotic syndrome. Here we report a patient with nephrotic syndrome developing disseminated strongyloidiasis after steroid treatment. Not only did he survive but there was resolution of nephrotic syndrome after treatment with thiabendazole. CASE REPORT A 55-year-old cleaning worker presented to our hospital in February 1997 because of progressive ankle swelling for 2 months. He was otherwise asymptomatic and did not have any chest or gastrointestinal symptoms. His past health was good. He did not smoke or drink. Physical examination showed only generalized edema. Further investigations showed features compatible with nephrotic syndrome. Results of initial screening for secondary causes were all negative (Table 1). Renal biopsy showed minor glomerular abnormality with mesangial hypercellularity (Fig 1). Immunofluorescence showed patchy small amounts of granular deposits of immunoglobulin M (IgM) and C3 in glomerular basement membrane. Electron microscopy of one glomerulus showed extensive fusion of the foot processes, mildly
increased mesangial cells and matrix, absence of electrondense deposit, and unremarkable basement membrane. Idiopathic glomerulonephritis was diagnosed. The patient was treated with salt restriction and diuretics. He consulted a private nephrologist, and prednisolone 20 mg twice daily was prescribed. He was admitted 6 weeks later into our hospital again because of epigastric pain, nausea, vomiting, and watery diarrhoea without blood or mucus. Physical examination indicated only edema and abdominal distension. Investigations showed the persistence of hypoalbuminemia, evidences of small bowel dilation in abdominal radiograph, and inflamed duodenum in upper endoscopy. There was raised serum IgE (419 IU/mL), but not eosinophilia. Conservative treatment was instituted initially. Because of the risk of sepsis, prednisolone was decreased to 10 mg daily initially and then tailed off gradually despite the presence of proteinuria and hypoalbuminemia in admission. A course of antibiotic therapy was also given. However, there was persistently high output from the Ryle’s tube. One-week later, duodenal biopsy showed strongyloides infestation (Fig 2). Thiabendazole was prescribed, and the patient’s condition responded promptly with resolution of intestinal obstruction in 1 week. Surprisingly, his nephrotic syndrome remitted after the eradication of strongyloides. There was progressive decrease in proteinuria in the following few months (latest ⫽ 0.29 g/d). Stool for strongyloides remained negative after treatment. One year later, the patient was still asymptomatic and not on any medication. The patient refused to have a second renal biopsy and defaulted further follow-up.
From the Departments of Medicine and Clinical Pathology, Tuen Mun Hospital, Hong Kong. Received December 4, 1998; accepted in revised form February 16, 1999. Address reprint requests to Yuk-kei Yee, MBBS, Department of Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3306-0036$3.00/0
American Journal of Kidney Diseases, Vol 33, No 6 (June), 1999: E4
1
2
YEE ET AL Table 1. Initial Laboratory Finding
Hemoglobin White cell count Platelet count ESR Urea Creatinine Albumin Urinary protein Creatinine clearance Cholesterol C3 C4 Anti-nuclear factor ANCA HbsAg Anti-HCV
14.9 g/dL 9.9 ⫻ 109/L 278 ⫻ 109/L 109 37.0 mg/dL 1.12 mg/dL 1.5 g/dL 9.45 g/d 80 mL/min 561 mg/dL 112 mg/dL* 34 mg/dL* Negative Negative Negative Negative
*Reference ranges of C3 and C4 are 88 to 201 and 16 to 47, respectively.
DISCUSSION
Strongyloides stercoralis is endemic in southeast Asia,2 including southern China. The local incidence is not available, but no case was found when the stool samples of over 80 renal patients were screened for the parasites in our center. The sensitivity of stool examination is just around 30%.3 Examination of multiple stool samples4 or use of enzyme-linked immunosorbent assay test to detect serum antibodies to Strongyloides5,6 improve the sensitivity. History of travel to endemic areas, as with our patient, increases the risk of this parasitic infection.
Strongyloides stercoralis is unique among human helminths in its capability of autoinfection. Humans get infected when the infective filariform larvae penetrate the skin or mucous membranes, usually as a result of contact with contaminated soil.7 The adult female, 2 mm long, usually resides in the mucosa of the upper jejunum. Parasitic males have not been observed. Females reproduce parthenogenetically. Because the level of autoinfection is usually low, chronic strongyloidiasis is usually asymptomatic and commonly not recognized. Disturbed host-parasite balance will accelerate autoinfection, resulting in hyperinfection with or without the presence of parasites outside the gastrointestinal or respiratory tract. Widespread invasion of filariform larvae into various organs, including the lung, liver, kidney, and even central nervous system, may occur. This results in hemorrhage, inflammation, and sepsis. Disseminated strongyloidiasis is diagnosed in this situation. However, hyperinfection syndrome and disseminated strongyloidiasis are commonly used interchangeably. Steroid is the most important cause of hyperinfection.8,9 Other predisposing factors include immunosuppression, acquired immunodeficiency syndrome, renal failure, diabetes mellitus, malnutrition, and achlorhydria.10-12 Because the manifestation is usually nonspecific, diagnosis is not uncommonly delayed, and mortality of disseminated strongyloidiasis is as high as 50% to 80%.2,8,13
Fig 1. Masson’s Trichrome stain of renal biopsy. There are focal mild to moderate mesangial proliferation and increase in matrix; patchy lymphoplasmacytic infiltrate in the stroma is also noted.
STRONGYLOIDES AND NEPHROTIC SYNDROME
3
Fig 2. H&E stain of duodenal biopsy. Duodenum was heavily infiltrated by neutrophils, lymphocytes, and plasma cells. Abundant parasitic worms were found, in both adult and larval forms.
Only early diagnosis and treatment can improve the prognosis. A high level of suspicion is necessary. Glomerular changes have been reported in patients with disseminated strongyloidosis.2 However, glomerulonephritis with nephrotic syndrome has not been reported in patients with chronic strongyloidiasis. In our case, the typical glomerular abnormalities of strongyloidiasis, such as mesangial hypercellularity and granular deposits of IgM and C3 in glomerular basement membrane, were noticed before the occurrence of disseminated strongyloidiasis. The nephrotic syndrome remitted after eradication of strongyloidiasis in this patient. These suggest that Strongyloides may be causally related to the glomerulonephritis. Immunofluorescence staining for parasitic antigens in the renal biopsy specimen is helpful in supporting this hypothesis, but it is not available in our laboratory. Reactive arthritis and uveitis secondary to strongyloides infection also have been reported. Rapid improvement after treatment with wormicide was observed.14 Parasitic glomerulopathies is now an important chapter in nephrology. Glomerulopathies have been noticed in patients with infection by malaria, schistosomiasis, filariasis, kala-azar, trypanosomiasis, toxoplasmosis, and echinococcosis.15 The clinical manifestation varies in different infections, ranging from abnormalities in urinalysis to proteinuria to renal failure. Renal
involvement can occur as a result of secondary amyloidosis or outflow tract obstruction. Nephrotic syndrome as a result of parasitic glomerulopathy has been reported only in malaria, schistosomiasis, filariasis, and cysticercosis.15,16 Immune complexes play a major role in the pathogenesis of these glomerulopathies. Recovery after successful treatment of the parasites have been reported in patients with falciparum malarial nephropathy, Class II schistosomal glomerulopathies, and cysticercosis-related nephrotic syndrome.15,16 In conclusion, Strongyloides may be responsible for the nephrotic syndrome in our patient because of the findings in renal biopsy, the time course of the development, and resolution of nephrotic syndrome after thiabendazole treatment. Nonetheless, reporting of similar cases and animal studies is needed to clarify this causal relationship. Moreover, the possibility of strongyloidiasis should be considered even in nonendemic areas such as Hong Kong, before and after the administration of steroid therapy, so as to prevent death from this potentially fatal disease. REFERENCES 1. Churg J, Bernstein J, Glassock RJ: Renal disease: Classification and Atlas of Glomerular Diseases (ed 2). Tokyo, Japan, Igaku-Shoin, 1995, pp 232-251 2. Cook GC: Strongyloides stercoralis hyperinfection syndrome: How often is it missed? Q J Med 244:625-629, 1987 3. Dreyer G, Fernandes-Silva E, Alves S, Rocha A, Albu-
4
querque R, Addiss D: Patterns of detection of Strongyloides stercoralis in stool specimens: Implications for diagnosis and clinical trials. J Clin Microbiol 34:2569-2571, 1996 4. Sato Y, Kobayashi J, Toma H, Shiroma Y: Efficacy of stool examination for detection of Strongyloides infection. Am J Trop Med Hyg 53:248-250, 1995 5. Neva FA: Biology and immunology of human strongyloidiasis. J Infect Dis 153:397-406, 1986 6. Lindo JF, Conway DJ, Atkins NS, Bianco AE, Robinson RD, Bundy DA: Prospective evaluation of enzymelinked immunosorbent assay and immunoblot methods for the diagnosis of endemic Strongyloides stercoralis infection. Am J Trop Med Hyg 51:175-179, 1994 7. Mahmoud AAF: Strongyloidiasis. CID 23: 949-953, 1996 8. Igra-Siegman Y, Kapila R, Sen P, Kaminski ZC, Louria DB: Syndrome of hyperinfection with Strongyloides stercoralis. Rev Infect Dis 3:397-407, 1981 9. Genta RM: Dysregulation of strongyloidiasis: A new hypothesis. Clin Microbiol Rev 5:345-355, 1992 10. Goannella RA, Broitman ZA, Zamcheck N: Influence
YEE ET AL
of gastric acidity on bacterial and parasitic enteric infections. Ann Intern Med 78:271-276, 1973 11. Hagelskjaer LH: A fatal case of systemic strongyloidiasis and review of the literature. Eur J Clin Microbiol Infect Dis 13:1069-1074, 1994 12. Lessnau KD, Can S, Talavera W: Disseminated Strongyloides stercoralis in human immunodeficiency virusinfected patients. Chest 104:119-122, 1993 13. Genta RM: Global prevalence of strongyloidiasis: Critical review with epidemiologic insights into the prevention of disseminated disease. Rev Infect Dis 11:755-767, 1989 14. Patey O, Bouhali R, Breuil J, Chapuis L, CourillonMallet A, Lafaix C: Arthritis associated with Strongyloides stercoralis. Scand J Infect Dis 22:233-236, 1990 15. Barsoum RS: Parasitic glomerulopathies. Proc R Coll Physicians Edinb 27:283-299, 1997 16. Rabenantoandro R, Rasoloarijaona L, Raharivelina C, et al: Extramembranous glomerulonephritis and cysticercosis. Sante 6:254-257, 1996.