Renal Amyloidosis: Epidemiological, Clinical, and Laboratory Profile in Adults from One Nephrology Center.

Background: Renal amyloidosis is one of the main differential diagnoses of nephrotic proteinuria in adults and the elderly. The aim of this study with the most important series in our country is to contribute to the epidemiological, clinical, and etiological study of the renal amyloidosis. Methods: In a retrospective study carried out between 1975 and 2019, 310 cases of histologically proven and typed renal amyloidosis were selected for this study. Results: There were 209 men and 101 women with a mean age of 53.8 ± 15.4 years (range, 17-84 years). Of the 310 cases, 255 (82.3%) were diagnosed with AA renal amyloidosis and 55 (17.7%) with non-AA amyloidosis. Infections were the main cause of AA amyloidosis, and tuberculosis was the most frequent etiology. The period from the onset of the underlying disease to diagnosis of the renal amyloidosis was an average of 177 months. The most frequent manifestations at the time of diagnosis were nephrotic syndrome (84%), chronic renal failure (30.3%), and end-stage renal disease (37.8%). After a medium follow-up of 16 months (range, 0-68 months), mortality occurred in 60 cases. Conclusions: Given the high frequency of AA amyloidosis in our country, awareness of the proper management of infectious and chronic inflammatory diseases remains a priority in reducing the occurrence of this serious disease.

New Markers of Bone Fragility in Hemodialysis Patients: A Monocentric Study.

INTRODUCTION: Mechanisms underlying bone fragility in patients under dialysis are various. The assessment of bone disorder is not yet codified in these patients. Our study aimed to determine the relationship between the serum fibroblast growth factor 23 (FGF23) level and bone fragility. We also aimed to assess the bone alkaline phosphatase (bAP) to the C-terminal telopeptide of type I (CTX) ratio and the FGF23*bAP product to CTX ratio in patients under hemodialysis. METHODOLOGY: We conducted a cross-sectional study, including 76 patients under hemodialysis. To assess bone fragility, we measured bAP, CTX, and FGF 23. We calculated the bAP to the CTX ratio (bAP/CTX) and the FGF23*bAP product to the CTX ratio (FGF23*bAP/CTX). We defined bone fragility as the existence of osteoporosis or fragility fractures. Receiver operating characteristic (ROC) curves were evaluated for each biological using the existence of osteoporosis or fragility fracture as the gold standard for bone fragility. RESULTS: There were 51 men. The mean age was 53.36 ± 14.27 years. Bone fragility was noted in 25 cases. Patients with osteoporosis had higher FGF*bAP/CTX and bAP/CTX ratios. The ability of the ratio (bAP/CTX) to distinguish patients with osteoporosis from those without osteoporosis was good, with a ROC AUC of 0.707. The optimal ratio cut-off value with the highest accuracy was 9.72. The ability of the ratio (FGF23*bAP/CTX) to distinguish patients with bone fragility was good, with a ROC AUC of 0.701. The optimal ratio cut-off value with the highest accuracy was 1621.89 (sensitivity 60%, specificity 78.4%). CONCLUSION: Our study showed FGF23, FGF23*bAP product to CTX ratio, and the bAP to CTX ratio can be used as markers of bone fragility in hemodialysis patients. Therefore, these noninvasive and relatively inexpensive methods may serve to diagnose bone fragility in patients under hemodialysis.

Renal Involvement in 2 Siblings With Cockayne Syndrome.

Renal involvement in Cockayne syndrome is rare and its pathogenesis is yet unknown. We report herein 2 cases (siblings) with Cockayne syndrome type A confirmed by biochemical and molecular assays. The first case was a 13-year-old girl who presented with nephritic syndrome and a rapidly progressive kidney failure. Her younger sister, 7 years old, exhibited hypertension, hyperfiltration, and microalbuminuria. She had hyperreninemia and hyperaldosteronemia without kidney failure or renal arterial stenosis. Renal biopsy, performed the older sister, revealed cystic focal segmental glomerulosclerosis, arteriosclerosis, tubulointerstitial fibrosis, and tubular atrophy. The different clinical phenotypes in the two siblings support the absence of an obvious genotype-phenotype correlation in Cockayne syndrome type A patients. In the older sister, the particular focal glomerular sclerosis and senile lesions assume that kidney disease in Cockayne syndrome may be related to prematurely aging secondary to a defective nucleotide repair.

Acute tubular necrosis following transurethral resection of the Prostate using Glycine as irrigating fluid.

Transurethral resection of the prostate is currently the gold standard for the surgical treatment of the benign prostatic hyperplasia. This surgery may lead transurethral resection of the prostate (TURP) syndrome and in some cases, acute tubular necrosis can develop. We report a patient who developed hyponatremia, hemolysis and oliguric acute renal failure as a major complication following TURP using glycine as irrigating fluid.A 64-year-old man was admitted for a prostate resection procedure. Physical examination revealed a healthy elderly man. Preoperative laboratory data showed serum sodium 140 mEq/L, blood urea nitrogen (BUN) 0.6 g/L, creatinine 0.7 mg/dL and hemoglobin 12.9 g/dL. Few hours after, the patient becomes incoherent and developed oliguria, nausea and vomiting. The laboratory data revealed rapidly elevating BUN and creatinine levels (BUN 2.4 g/L; creatinine 6.1 mg/dL), the serum sodium concentration decreased by 14 meq/L. A decreased hemoglobin level (7.4 g/dL) with an elevated lactate dehydrogenase level (665 U/L) was observed. Renal ultrasonography was normal. The diagnosis of acute tubular necrosis complicating TURP syndrome was retained. The hyponatremia was slowly corrected to 132 mmol/L by diuresis and fluid restriction. The renal function recovered after four hemodialysis sessions. Using glycine as an irrigant for TURP may cause hyponatremia, hemolysis and also acute renal failure, especially in patients with longer resection time. It is necessary to carry out every effort to shorten resection time and avoid extravasation during surgery.

Malignant hypertension-associated thrombotic microangiopathy following cocaine use.

Cocaine is one of the most commonly used illicit drugs with distribution and consumption throughout the world. Acute renal failure associated with rhabdomyolysis, direct vasoconstriction and hemodynamic alteration is well described in patients with cocaine intoxication. Cocaine use is associated with high blood pressure and may rarely induce malignant hypertension associated with thrombotic microangiopathy. We report the case of a patient who developed malignant hypertension associated with thrombotic microangiopathy after chronic consumption of cocaine. A kidney biopsy revealed thrombotic microangiopathy with fibrinoid necrosis of arterioles and glomerular tufts. He required dialysis sessions. Cocaine-mediated endothelial injury and platelet activation may play important pathogenetic roles in cocaine abusers who develop malignant hypertension associated with thrombotic microangiopathy. Clinicians need to be aware of this rare feature of cocaine intoxication.

The tunneled catheter for haemodialysis: about 52 cases.

BACKGROUND: Vascular access is a basic and essential tool required for performing renal replacement therapy in end stage renal disease. AIM: To study the indications of tunneled catheter (KTT) in hemodialysis (HD), identify complications related to the use of KTT and contributing factors, assess the survival and performance of the technique. INTRODUCTION: The making of a vascular access is an angular piece for adequate HD and in good conditions. In this context the KTT may be an alternative. METHODS: A retrospective study of 52 KTT placed in 49 patients collected in the department of Nephrology Dialysis and Renal Transplantation in RABTA Tunis between 2008 and 2011. RESULTS: The average age of our patients was 55.58 years ± 13.5 years, their Sex ratio was 0.79. The Thirty of our patients were diabetic, 46.2% had hypertension and 21.2% had underlying cardiac disease. The mean duration of HD was 1111.35 days or 37 months. The most common indication of KTT was the absence of arteriovenous fistula in 65.4% of cases, other indications were: short survival (30.7%), the exhaustion of venous capital (34.6%), mediacalcosis (34.6%) and immunosuppression (36.5%). The right internal jugular vein was the choice of insertion site with 78.8%. The overall incidence of immediate complications was 19.2%. Among our patients, 31.4% had a dysfunction. The period of HD represent the risk factor for dysfunction KTT (p = 0.006).An infectious complication was observed in 29% of cases. The median time to onset of infection was 190.83 days. Staphylococcus was isolated in 40% of cases. The average duration of use of KTT was 238 days. The only single factor determining the survival of KTT was the number of KTT put in the same patient. CONCLUSION: More than a quarter of the population are dialyzed through a catheter. Despite concerted efforts, much remains to be done for the confection at time of a permanent vascular access.

The pattern of histologically-proven acute post-infectious glomerulonephritis in Tunisian adults seen in 1976-2004.

INTRODUCTION: Acute post-infectious glomerulonephritis (APIGN) is uncommon in adults. It is widely recognized that the prognosis of APIGN is good in children. There is however little information about its long-term prognosis in adults. METHODS: Between December 1976 and October 2004, 148 adult cases of APIGN were managed in our center. We retrospectively reviewed these patients' records and evaluated their clinical course and outcome. RESULTS: The mean age of studied patients was 36 ± 15 years, and the male to female ratio was 2.3. The most common site of preceding infection was the respiratory tract (68.8%). At presentation, 89.2% had nephritic syndrome and 9.4% had rapidly progressive glomerulonephritis. Proteinuria was observed in 99.3%, hematuria in 95.3%, peripheral edema in 89.2% and hypertension in 81.8%. Most patients (60.7%) had acute kidney injury and four patients (2.7%) required dialysis. Renal biopsy showed diffuse endocapillary proliferative glomerulonephritis in 88.8% of patients, associated with extracapillary proliferation in 12%. After a median follow-up of 2.5 year, only two patients died and 16.12% of patients had persistent clinical and/or biological abnormality. Chronic kidney disease was noted in 10 patients (6.75%) including four patients (2.7%) who progressed to end-stage renal disease. Poor prognostic factors included nephrotic range proteinuria, extracapillary proliferation in renal biopsy, acute kidney injury and the need for dialysis. CONCLUSION: In this cohort of patients, APIGN progressed to chronic kidney disease in less than 10% of patients.

[Etiologic profile of amyloidosis of the elderly in Tunisia]. / Profil étiologique de l'amylose en Tunisie chez les sujets âgés.

BACKGROUND: The amyloidosis is one of the histologic lesions the most frequently associated to the aging. AIM: To identify the several etiologies of amyloidosis in elderly patients according to immunohistochemical type. METHODS: Retrospective study on 10 years, in Internal medicine and Nephrology department in Charles Nicolle Hospital. Tunis. Tunisia. Diagnosis of amyloidosis was retained after histological confirmation with specific colorations, in patients aged 65 years or more at the diagnose of amyloidosis. RESULTS: The study enrolled 51 patients with amyloidosis. In 67% of cases it was AA amyloidosis. The etiology the most frequently observed with this type was the tuberculosis, followed by chronic pulmonary infections. We retained diagnose of non AA amyloidosis in 21% of patients. The multiple myeloma has been the most frequent etiology observed, but no cause was identified at about half of patients. Twelve per cent of amyloidosis were not typed. CONCLUSION: From our study, we can remark the high predominance of AA amyloidosis, probably because of frequency of tuberculosis which is still high in our country, this is not in accordance with occidental data, were AL amyloidosis and senile amyloidosis predominate in elderly.

Histopathological spectrum of childhood idiopathic steroid-resistant nephrotic syndrome in Tunisia.

BACKGROUND: In children, renal biopsy is routinely required in the management of idiopathic steroid-resistant nephrotic syndrome particularly prior to starting nephrotoxic immunosuppressive agents. AIM: To investigate the correlations between the results of initial renal biopsy in Tunisian children with idiopathic steroid-resistant nephrotic syndrome and the subsequent response to cyclosporineprednisolone combination. METHODS: We conducted a retrospective study of children with idiopathic steroid-resistant nephrotic syndrome over the period 2002- 2009. Data on clinico-biological features, histological diagnosis and response to cyclosporine-prednisolone were collected. RESULTS: Thirty patients were enrolled, of whom 16 had focal segmental glomerulosclerosis, eight had minimal change disease and six had diffuse mesangial proliferation. Complete Remission was achieved in 15 patients (50%). Nine patients (30%) went into partial remission. Only six patients presented no response (20%). No statistically significant relationship between the different pathological types and the response to CsA-prednisone was found. CONCLUSION: In our study, two important facts were noted: 1) the predominant histopathological subtype was the focal segmental glomerulosclerosis; 2) a high remission rate was achieved in our patients using a combined cyclosporine-prednisolone treatment regimen. This response is not dependent on the histological type.

[A rare cause of pruritus in an hemodialysed patient]. / Une Cause Rare de Prurit chez une Hémodialysée Chronique.

BACKGROUND: Uremic pruritus is frequent in patients undergoing hemodialysis. It's multifactorial secondary in most cases to metabolic complications related to uremia. AIM: We report a rare cause of pruritus in an haemodialysed patient. OBSERVATION: It's a 48-year-old woman in periodic haemodialysis during 17 years. She suffered from generalized pruritus associated with psychiatric disturbance without neurologic deficits. CT scan and magnetic resonance imaging revealed extensive, diffuse and bilateral involvement of the white matter. The diagnosis of large low grade B cell lymphoma was confirmed by the histologic examination of stereotactic biopsy which leads to early intracranial hemorrhage and death. CONCLUSION: Before attributing pruritus to renal failure, one should exclude other causes such as the NHL even rarely reported especially when it associated with psychiatric disturbances. CT scan and magnetic resonance imaging contribute to diagnosis.

[Calciphylaxis in chronic renal failure: 3 cases]. / Calciphylaxie au cours de l'insuffisance rénale chronique: etude de 3 cas.

BACKGROUND: Calciphylaxis is a small vessel disease responsible for vascular calcification and skin necrosis. It occurs in association with chronic renal failure and has a poor prognosis. BUT: Report new cases. We report 3 cases of calciphylaxis occurred in patients with chronic renal failure secondary to interstitial nephritis in 1 case, diabetic nephropathy in 1 case and thrombotic microangiopathy in 1 case. CASES: They were 2 females an 1 man aged of 44, 3 years meanly. Hyperphosphoremia and hyperparathyroidism were the essential risk factors. All patients died by sepsis. This course was precipitating by corticotherapy in 2 cases. CONCLUSION: Early recognition and treatment of risk factors is mandatory to reduce mortality in uremic patients with calciphylaxis.

[Renal amyloidosis during Behçet's disease. Study of one case]. / Amylose compliquant une maladie de Behçet: a propos d'un nouveau cas.

BACKGROUND: Amyloidosis in Behçet's disease is rare and has a poor outcome. AIM: Report a new case. CASE: We report a case of a 38-year-old Tunisian woman who presented with Behçet's disease and nephrotic syndrome. Renal biopsy showed amyloid deposition consistent with AA type. She had not any associated disease that might be an additional cause of secondary amyloidosis. She was treated by colchicine. After 3 years, proteinuria had disappeared and persisted negative 11 years after the diagnosis. A second renal biopsy showed the persistence of amyloidosis. CONCLUSION: As amyloidosis is one of the prognostic factors affecting survival in Behçet's disease, patients with this disease should be screened for amyloidosis. Administration of colchicine to these patients may be beneficial.

[Vascular trombosis of renal graft: 9 cases]. / Thromboses vasculaires du greffon apres transplantation renale: a propos de 9 cas.

BACKGROUND: Allograft renal thrombosis can occur in 1 to 6% of cases. Many predisposing factors has been identified especially alteration of coagulation. AIM: We analyzed in this study frequency and predisposing factors of renal graft thrombosis. METHODS: We report a retrospective study including 319 renal transplant recipients. RESULTS: Nine patients (2.8%) presented veinous graft thrombosis in 5 cases and arterial thombosis in 4 cases. There were 6 men and 3 women aged of 30.6 years meanly (10-56) which developed the thrombosis 6 days (1-48) after the transplantation. All patients were detransplanted after 16.2 days and 1 patient died. CONCLUSION: Thrombosis constitute an important cause of graft loss. A perfect surgical technic and prophylactic treatment in high risk patients are necessary to reduce this complication.

[Membranoproliferative glomerulonephritis in patients with cryoglobulinemia complicating hepatitis C virus: report of 11 cases]. / Glomérulonéphrite membranoproliférative secondaire à une cryoglobulinémie mixte compliquant une hépatite virale C: a propos de 11 cas.

BACKGROUND: Membranoproliferative glomerulonephritis in patients with cryoglobulinemia complicating hepatitis C virus have yet been reported. Although, it remains controversial, antiviral treatment seems to be able to improve the outcome of glomerulonephritis. AIM: The objectives of the study were to analyze characteristics of this association and to report literature data and newness treatment. METHODS: It's a retrospective study including 11 patients with membranoproliferative glomerulonephritis, hepatitis C virus and mixed cryoglobulinemia. Hepatitis C virus antibodies was identified by ELISA technique. Hepatitis C virus genotype was identified in one patient. Cryoglobulins were isolated from sera of all patients at 37 degrees Celsius. RESULTS: Patients were 3 men and 8 women with a mean age of 51.9 +/- 15.5 years. Between the 11 patients, 7 had hypertension, 9 had nephrotic syndrome and 10 had chronic renal failure. Renal biopsy showed membranoproliferative glomerulonephritis lesions in all cases with fibrinoid thrombi in 8 cases. Six patients had chronic liver disease. Liver biopsy was performed in 4 patients, showing histological feature compatible with chronic active hepatitis in 2 cases. No patient had antiviral therapy. Renal failure was stable in 5 cases and progressed in 6 cases with end stage renal failure in 3 of them. One patient died, 4 months after diagnosis, because of severe pulmonary involvement in cryoglobulinemic vasculitis. In literature, treatment is dominated by antiviral therapy composed first by Interferon Alpha alone. Combination therapy associating Interferon and Ribavirin was recently used in renal involvement; it is clearly more effective than interferon alpha alone. CONCLUSION: Hepatitis C virus detection should be performed when membranoproliferative glomerulonephritis is associated with cryoglobulinemia. Antiviral treatment should be more widely used in Tunisia to evaluate his effect on renal involvement

[Treatment of uremic patients by automated peritoneal dialysis: study of 78 cases]. / Prise en charge des patients urémiques en dialyse péritonéale automatisée : a propos de 78 cas.

BACKGROUND: Automated peritoneal dialysis has been increasingly used in recent years. The quality of life is improved in patients on automated peritoneal dialysis with more time for work, family and social activities compared to patients on continuous ambulatory peritoneal dialysis. AIM: We report our experience concerning patients on continuous ambulatory peritoneal dialysis. METHODS: From July 1997 to June 2003, we review retrospectively 78 patients with chronic renal failure treated by automated peritoneal dialysis. Tenckhoff catheter was used for all patients with 1 cuff in 39 cases (35.5%) and 2 cuffs in 71 cases (64.5%). RESULTS: There were 46 males and 32 females. Their mean age was 38.6 +/- 14.5 years. Their main nephropathies were glomerular in 23 patients (29.%), diabetic in 20 patients (25.6%) and vascular in 19 patients (24.4%). Among the 78 patients, 61 (78.2%) were autonomous while 17 (21.8%) were assisted by a member of their family. The mean period of therapy was 25.5 months (3 to 61 months). Peritonitis was the main complication, it was observed in 45 cases after a mean delay of 17 months (1 to 38 months). The mean rate of peritonitis was 36.5 months/patient. Their etiology was identified in 21 (46.7%) cases (8 septic manipulations of catheter and 13 tunnel infections). The principal organism isolated in peritoneal fluid were 18 gram-positive cocci (13 staphylococcus aureus, 4 coagulase-negative staphylococci, 1 streptococcus) and 10 gram-negative bacilli. The outcome of peritonitis was favourable in 39 cases (86.7%). The actuarial technique survival at 1, 3 and 5 years was respectively 94.6%, 80.1% et 49.3%. The actuarial patient survival at 1, 3 and 5 years was respectively 93.3%, 76.8% et 52.2%. At the end of the study, 43 patients (56.4%) left the automated peritoneal dialysis program: 22 (28.2%) were shifted to hemodialysis, 15 (19.3%) died, 6 (7.7%) were transplanted and 1 patient (1.3%) was shifted to continuous ambulatory peritoneal dialysis. CONCLUSION: Our experience concerning automated peritoneal dialysis is recent with a small number of patients. Our results were acceptable and we have to encourage and extend automated peritoneal dialysis to the most new patients with end-stage renal failure.

[Epidemiology of end-stage renal disease before starting hemodialysis and factors influencing hemodialysis survival]. / Epidemiologie de l'insuffisance renale chronique terminale avant l'initiation de l'hemodialyse et les facteurs influençant la survie en hemodialyse.

BACKGROUND: The incidence of end-stage renal failure is high and it is responsible for the increase of the rate of morbidity and mortality rates among our patients. AIM: The objective is to study patient characteristics before starting hemodialysis and to evaluate factors influencing their short and long term survival. METHODS: This is a prospective study of 127 patients starting hemodialysis between June and December 2001. On May 31, 2005, their survival was analyzed according to different parameters. RESULTS: Patients were 77 males and 50 females. Their mean age was 51.4 +/- 16.1 years (15 to 78 years). Diabetes was observed in 33.9% of cases. Only 70.9% of patients were covered by a social service. Chronic renal failure was diagnosed at the end stage in 34.6% of cases. Before starting hemodialysis, only 4 patients were vaccinated against B hepatitis and arteriovenous fistula were not made in any patients. Pericarditis was observed in 9.4% of patients. Albuminemia was < 35 g/l in 60.5% of patients. First hemodialysis session was programmed in 53.5% of patients and realized urgently in 46.3% of patients. Patients were hemodialysed 4, 8 and 12 hours per week respectively in 16.5%, 15.8% and 67.7% of cases. On May 31, 2005, 35.4% of patients died. Their actuarial survivals at 3 months, 1 year and 4 years were respectively at 87.5%, 79.5% and 64.4%. Acturial survival was bad in patients with pericarditis, diabetes, hemodialysed less than 12 hours/week and when the first hemodialysis session was started urgently. CONCLUSION: The diagnosis of renal failure was frequently made at end-stage. There are no preparations before starting hemodialysis. We have to reinforce prevention programmes and increase the number of nephrologists and nephrology departments.

[Acute renal failure in a prisoner after hunger strike]. / Insuffisance renale aigue survenue chez un detenu suite a une greve de la faim.

BACKGROUND: Acute renal failure may occur in varied circumstances. It is potentially reversible spontaneously or after specific treatment. It is rare after hunger strike and fewer cases were reported in the literature. The physiopathological mechanisms are varied and remain incompletely known. AIM: We report the case of a prisoner having presented an acute renal failure after a hunger strike wich was completely reversible. CASE: He's a 29 year old man, without a past medical facts, in July 2004 he was incarcereted in prison. In October 2004 he undertake a hunger strike during one month. In November 2004 he was hospitalized for global dehydration and shock. His physical examination showed blood pressure 60/40 mmHg, weight 59 Kg with a loss of weight about 10 Kg, diuresis 800 cc/day. His biological findings showed urea 100 mmol/l, creatinemia 679 (mo/l, natremia 179 mmol/l, kaliemia 5 mmol/l, glycemia 5.2 mmol/l, albuminemia 35 g/l, calcemia 2.35 mmol/l and biological marques of rhabdomyolysis: CPK at 11 times the normal and LDH two times the normal. His treatment consisted on rehydratation, parenteral then enteral refeeding and psychiatric talks. The evolution was favourable, re-establishment of good hydration state with a gain weight of 7 Kg, normalization of renal function, his creatininemia reached 85 (mol/l in three weeks and normalization of muscles enzymes in one month. CONCLUSION: Hunger strike continue to pose a problem because of it's frequency in penitentiary structures and its organic disorders which can lead to death. A good psychiatric cares may be undertaked in order to prevent a such bad manifestations.

[Myeloma, Kaposi's sarcoma and HHV8 infection in hemodialyzed patient]. / Myelome multiple, maladie de Kaposi et infection par le HHV8 chez un hemodialyse chronique.

BACKGROUND: The association between Kaposi's sarcoma, Human Herpes Virus 8 infection and multiple myeloma is still controversial especially in hemodialysed patient. AIM: report a new case of this association. OBSERVATION: We report the case of a 83 year old man in whom the diagnosis of multiple myeloma of IgA/kappa had been made in December 2003 with end stage renal failure requiring hemodialysis. Initially, it had been treated with Melphalan, Cyclophosphamide, Prednisolone and Vincristine and secondary by Melphalan and Prednisone. Three months later, he had developed extensive porpour lesions in his lower limbs. Skin biopsy had been informed of Kaposi's sarcoma. Human Herpes Virus 8 test was positive. CONCLUSION: Our observation is another case supporting the hypothesis that Kaposi's sarcoma and multiple myeloma share a common aetiology such as Human Herpes Virus 8. The immunodepressed state related to aging, multiple myeloma, chemotherapy and hemodialysis was the probable factor responsible of rapidly progressive Kaposi's sarcoma in our patient. The association myeloma and Human Herpes Virus 8 infection is still controversial.