Renal cancer and malformations in relatives of patients with Bardet-Biedl syndrome.

BACKGROUND: Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with five loci identified thus far. The spectrum of disease includes diverse malformations of the kidney and lower urinary tract. The incidence of BBS is approximately 1/100,000 with a predicted heterozygote frequency of 1/160, and it has been suggested that heterozygotes are at increased risk of obesity and hypertension. METHODS: We describe renal disease in relatives of 109 UK BBS patients. Using PCR with fluorescent microsatellite markers we amplified DNA derived from renal tumours of affected parents to determine whether there was loss of heterozygosity at any of four BBS loci and two other gene loci associated with clear cell renal cell carcinoma (CC-RCC). RESULTS: CC-RCC was diagnosed in three of 180 BBS parents and there was loss of heterozygosity at BBS1 (11q13) in the tumour tissue of one of these subjects. In addition, there was a high incidence of renal agenesis in siblings of BBS patients and two BBS families were identified with apparently dominant inheritance of renal malformations. In one family we were able to demonstrate that renal malformations segregated with the BBS2 locus (16q21). CONCLUSIONS: Since all parents and two-thirds of siblings of BBS patients must be heterozygous for BBS mutations, our observations may implicate BBS genes in the pathogenesis of both renal cancer and malformations, both disorders of precursor cell growth and differentiation. We suggest these observations may have important implications for screening potential BBS carriers for kidney disease and may lead to a greater understanding of the aetiology of renal disease in the general population.     

Renal transplantation in Bardet–Biedl Syndrome

Background

Renal anomalies are common in patients with Bardet–Biedl syndrome (BBS), a renal cystic ciliopathy with multi-systemic features. Renal transplantation is indicated in cases of end-stage renal disease (ESRD), but transplant centers may be hesitant to perform the necessary transplant in light of the multitude of metabolic comorbidities these patients often face with the potential to complicate outcomes.

Methods

Data from the Clinical Registry Investigating BBS (CRIBBS) were used to investigate renal transplant outcomes in the largest BBS cohort described to date.

Results

Of the 206 patients enrolled in the CRIBBS, 21 children (10.2 %; 16 girls, 5 boys; median age 8.4 years) had been diagnosed with ESRD. Renal transplantation was performed in 18 of these individuals between 1982 and 2015, including repeat transplantation in some cases, for a total of 22 kidneys. Overall graft survival was 81.6 % at 1 year post-transplantation, 75.7 % at 5 years, 59 % at 10 years, and 49.2 % at 25 years. Patient survival was 94.4 % at 1 year post-transplantation, 87.2 % at 8 years, and 79.3 % at 25 years.

Conclusions

At a median follow-up time of 97 months, relatively few complications of renal transplantation were reported in the patients of this study. However, body mass index was significantly elevated in transplanted individuals compared to non-transplanted individuals participating in CRIBBS at the most recent follow-up. Although the frequency of obesity and other manifestations of the metabolic syndrome warrant meticulous management in this high-risk population, favorable long-term outcomes suggest that renal transplantation is a viable option for patients with BBS and ESRD.

     

Renal vascular abnormalities in Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder. Specific diagnostic criteria for BBS have now been defined. At least four of the five cardinal signs of mental retardation, obesity, hypogenitalism in men, distal limb anomalies, and progressive tapetoretinal degeneration of the retina are required for the diagnosis. Renal involvement has been described as a sixth cardinal feature. Chronic renal failure occurs in 30%–60% of patients. Hypertension has been noted in 50%–66% of cases. Renal abnormalities reflect a defect in maturation of the kidneys. We present a patient with BBS who had bilateral microaneurysms and occlusions in renal arterioles. Received: 18 January 1999 / Revised: 18 May 1999 / Accepted: 21 May 1999     

Treatment of oropharyngeal cancer in renal transplant recipients without cessation of immunosuppressive therapy

INTRODUCTION: Renal transplantation and immunosuppression are associated with an increased incidence of malignancy. Reduction or cessation of immunosuppressive therapy has been advocated in these cases to prevent tumor progression and recurrence. We evaluated the outcome of treatment of oropharyngeal cancer (OC) after renal transplantation without cessation of immunosuppressive therapy. METHODS: The database of patients with OC after renal transplantation was analyzed with respect to age, sex, type of immunosuppression, interval between transplantation and diagnosis of cancer, as well as method of treatment and survival. RESULTS: Thirty one (2.06%) renal transplant recipients developed malignancy including 6 (20%) with OC. Lingual cancer was seen in three, and one each showed an isolated tonsillar lymphoma, a parotid carcinoma, or a carcinoma of the larynx with only the last having had two other malignancies in the past. Three subjects were on immunosuppression with azathioprine and prednisolone, and the others were prescribed cyclosporine and prednisolone. Average time from transplantation to diagnosis of OC was 106 months. The interval was the shortest (2 years) for tonsillar lymphoma in an 18-year-old patient who received cyclosporine and showed features of left follicular tonsillitis. The patient with advanced carcinoma of the larynx did not receive any treatment and succumbed within 3 months. The dose of cyclosporine was reduced in the lymphoma case but immunosuppression was not altered in the other patients. All subjects were treated with a standard protocol. During a mean follow-up of 33 months, one had local recurrence of parotid carcinoma and the others showed well functioning renal grafts. CONCLUSION: Comprehensive treatment of OC after renal transplantation without withdrawing the immunosuppression prolonged the life of these patients with functioning grafts.     

Bardet–Biedl syndrome: beyond the cilium

The Bardet–Biedl syndrome (BBS) is a significant genetic cause of chronic and end-stage renal failure in children. Despite being a relatively rare recessive condition, BBS has come to prominence during the past few years owing to revelations of primary cilia dysfunction underlying pathogenesis. The study of this multi-system disorder, which includes obesity, cognitive impairment, genito-urinary tract malformations and limb deformities, is beginning to reveal insights into several aspects of mammalian development and organogenesis. Involvement of BBS proteins in disparate pathways such as the non-canonical Wnt and Sonic Hedgehog pathways is highlighting their interplay in disease pathogenesis. Here we review the recent developments in this emerging field, with the emphasis on the renal component of the syndrome and potential future directions.     

Pure red cell aplasia preceding malignant lymphoma in a renal transplant patient

Malignant disorders are one of the major causes of morbidity and mortality in transplant patients. We present herein a renal transplant recipient with malignant lymphoma which preceded by pure red cell aplasia (PRCA). Acquired PRCA is a rare hematologic disorder in renal transplant recipients. It has been associated with a variety of disorders of immunologic dysfunction and neoplasms, exposure to drugs and toxins, infectious diseases, pregnancy and severe nutritional deficiency. This is the first case with PRCA preceding the malign lymphoma in a renal transplant patient. Treatment of lymphoma and lymphoma-related humoral and cellular changes or other undefined effects that may be related to therapy may be responsible of the resolving of PRCA in this patient. In this regard, renal transplant patients with acquired PRCA, must be closely followed for an underlying neoplastic disorder.     

Cost of Paid Transplantation Abroad: Possible Donor-Origin Early Multiple Myeloma in a Renal Transplant Recipient Treated Using Bortezomib

The incidence of cancer is greater in transplant recipients compared with the general population. Posttransplantation lymphoproliferative disorder (PTLD) is the second most common cancer in these patients. Non-Hodgkin lymphoma is most commonly observed, and multiple myeloma (PTLD-MM) accounts for less than 4% of PTLDs. Most reported PTLD-MM is of recipient origin, and to date, few cases of donor-origin PTLD-MM have been reported. Bortezomib is a protease inhibitor that has been used successfully to treat multiple myeloma. Herein, we describe the case of a patient in whom multiple myeloma developed shortly after paid living-unrelated renal transplantation performed abroad (in Egypt). The patient had no apparent risk factors for PTLD-MM. Thus, it was supposed that PTLD-MM was of donor origin, considering its early development, lack of recipient risk factors, and no available donor medical status. To our knowledge, this report is the first to describe the use of bortezomib in this setting. Although bortezomib plus dexamethasone therapy resulted in hematologic remission, the patient remained dialysis-dependent.     

Bardet-Biedl syndrome gene variants are associated with both childhood and adult common obesity in French Caucasians

Bardet-Biedl syndrome (BBS) is a rare developmental disorder with the cardinal features of abdominal obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, hypertension, and diabetes. BBS is genetically heterogeneous, with nine genes identified to date and evidence for additional loci. In this study, we performed mutation analysis of the coding and conserved regions of BBS1, BBS2, BBS4, and BBS6 in 48 French Caucasian individuals. Among the 36 variants identified, 12 were selected and genotyped in 1,943 French-Caucasian case subjects and 1,299 French-Caucasian nonobese nondiabetic control subjects. Variants in BBS2, BBS4, and BBS6 showed evidence of association with common obesity in an age-dependent manner, the BBS2 single nucleotide polymorphism (SNP) being associated with common adult obesity (P = 0.0005) and the BBS4 and BBS6 SNPs being associated with common early-onset childhood obesity (P = 0.0003) and common adult morbid obesity (0.0003 < P < 0.007). The association of the BBS4 rs7178130 variant was found to be supported by transmission disequilibrium testing (P = 0.006). The BBS6 variants also showed nominal evidence of association with quantitative components of the metabolic syndrome (e.g., dyslipidemia, hyperglycemia), a complication previously described in BBS patients. In summary, our preliminary data suggest that variations at BBS genes are associated with risk of common obesity.     

Abdominal computed tomography findings of malignant tumors in patients with solid organ transplants

AIMS: Incidence of malignancy in solid organ transplant recipients is higher compared to the general population. The aim of this study was to characterize distribution and appearance of abdominal malignant tumors detected with spiral computed tomography (CT) examination in patients with solid organ transplantation. MATERIALS AND METHODS: Between July 1994 and April 2006, 198 patients underwent liver transplantation and 568 patients underwent renal transplantation in our center. The abdominal CT studies were reviewed to determine the presence or absence of abdominal malignancy. All abdominal CT examinations were performed prior to immunomodulation or chemotherapy. RESULTS: Eleven renal and one liver transplantation patient developed an abdominal malignancy. Among 11 renal transplantation patients eight were diagnosed as abdominal Kaposi's sarcoma (KS) and three as posttransplantation lymphoproliferative disorder (PTLD) upon spiral CT examination. In two patients the transplanted organ itself had malignant tumors: one patient had PTLD with Burkitt lymphoma in the transplanted liver and the other a renal cell carcinoma in the transplanted kidney. Abdominal PTLD and KS showed imaging findings and the site of organ involvement somewhat different from nontransplant patients. The most common pathologies in KS were liver lesions (n=6) and lymphadenopathy (n=6). But in abdominal PTLD, the spleen (n=3) was the most involved organ. CONCLUSIONS: The early diagnosis of abdominal malignancies after solid organ transplantation is crucial for the patient's prognosis, especially under immunosuppression. The abdominal spiral CT examination was an effective modality to depict a malignancy among patients with solid organ transplantation.     

Posttransplant lymphoproliferative disorders in transplant recipients

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation, with a reported incidence between 0.8% and 32%. The incidence of PTLD mainly depends on the transplanted organ, the immunosuppressive drugs, the viral serology, and the age of the recipient. The aim of our study was to analyze our patients diagnosed with PTLD. Among 1040 transplantations, including 931 renal, 14 heart, 55 liver and 40 allogeneic peripheral blood stem cell (PBSC), 8 patients (7 male, 1 female) were diagnosed with PTLD. Five patients had undergone renal, one cardiac, one liver, and one PBSC transplantations. Four patients were diagnosed within the first year of transplantation. Six patients presented with abdominal disease, one with convulsions, and one with peripheral lymph node involvement. According to the World Health Organization classification system, six patients were diagnosed as diffuse large B-cell lymphoma, one patient Burkitt's lymphoma, and one polymorphic PTLD. At the time of diagnosis, 7 patients showed positive Epstein-Barr virus (EBV) and cytomegalovirus (CMV) Ig G and negative Ig M; one patient, positive EBV Ig M and negative CMV Ig G and M. EBV viral load was extremely high in the plasma of two patients by polymerase chain reaction. One of these patient's pathologic tissue revealed positive EBV DNA, which was not detected in six of the other eight patients. This patient was an 8-year-old boy diagnosed with Burkitt's lymphoma at 31 months after liver transplantation. Seven patients died of disease or complications of chemotherapy. Only one patient survived after the diagnosis of PTLD. In conclusion, even with treatment the mortality rate was high among our patients with PTLD. To decrease the incidence of PTLD and related mortality, risk factors must be evaluated in multicenter studies.     

A case report: hepatic posttransplant lymphoproliferative disorder in a non-liver transplant patient

Posttransplant lymphoproliferative disorder (PTLD) is the most common malignancy in children after solid organ transplantation. We present a patient, who developed Epstein-Barr virus (EBV)-related PTLD in the liver after renal transplantation. A 10-year-old EBV-seronegative boy with cystinosis underwent a living related preemptive renal transplantation. He received antiviral prophylaxis with valacyclovir. At 5.5 months posttransplantation he displayed a primary EBV infection with an high fever, hepatosplenomegaly, monocytosis, and positive EBV DNA levels. Two months there after, a hypoechoic nodular 20-mm lesion in the left lobe of liver was detected on abdominal ultrasonography, performed because of anorexia and weight loss. EBV-DNA copy number was 7820 copies per milliliter. Liver biopsy showed a diffuse large B-cell lymphoma that was compatible with PTLD. We stopped all immunosupressive agents other than prednisolone. Chemotherapy consisting of two courses of cyclophosphamide, vincristine, prednisolone, and adriamycin was followed by rituximab. Within 2 months, the lesion resolved and within 18 months, he was free of disease.     

A late-onset Epstein-Barr virus-related lymphoma completely remitted in a child with renal allograft

Lymphomas are frequently encountered malignancies following renal transplantations. A 17-year-old boy was found to have lymphoma 1.5 years after a the first cadaveric transplantation performed due to reflux nephropathy. Polyclonal anti-thymocyte globulin (induction) with prednisolone (PRD), azathioprine (AZT), and tacrolimus (Tac) regimen had been given after the transplantation. A hypoechoic mass (25 mm) was detected in the upper pole of the allograft by renal Doppler ultrasound performed due to graft dysfunction with a high basal serum creatinine (Cr) (2.2 mg/dL). The renal biopsy revealed a large B-cell lymphoma with CD20 staining in the medulla. The serum displayed a positive Epstein-Barr virus (EBV), immunoglobulin (Ig)G, negative IgM with negative DNA-polymerase chain reaction. However, the biopsy was positive for EBV-LMA. The viral status at the time of transplant was unknown. After withdrawing AZT and Tac therapies, a chemoimmunotherapeutic regimen consisting of PRD, cyclophosphamide, and anti-CD20 monoclonal antibody was administered twice. The patient excreted the necrosed tumor particles over a 2-month interval with hydronephrotic colic attacks. The basal Cr improved at 6 months (to 1.4 mg/dL). A low dose of Tac (0.5 mg/d) was added to PRD. The patient has remained in complete remission for 2.5 years with a well-functioning renal allograft. Although this case was a late-onset lymphoma, the patient displayed a picture like excreting stones from the allograft and remitted completely. This case illustrates that localization of a tumor may play a more important role than the elapsed time from transplant in the diagnosis in EBV-related posttransplant lymphoproliferative disease.     

Improvement of sleep‐related breathing disorder in patients with end‐stage renal disease after kidney transplantation

Lee JJ, Kim GS, Kim JA, Kim S‐J, Kang JG, Kim GH, Jung HH. Improvement of sleep‐related breathing disorder in patients with end‐stage renal disease after kidney transplantation.
Clin Transplant 2011: 25: 126–130. © 2009 John Wiley & Sons A/S. Abstract: Sleep‐related breathing disorder (SRBD) is a common symptom of end‐stage renal disease (ESRD). The aim of this study was to determine whether kidney transplantation improves SRBD. Twenty‐four patients with ESRD, who were admitted for kidney transplantation, underwent a sleep study using a portable ventilation effort recorder on the night before transplantation. Of these patients, 20 could repeat the overnight monitoring two wk after the transplantation. The median apnea‐hypopnea index (AHI) of the 20 patients was 13.5 (range, 2–40), and significantly reduced to 4.5 (range, 0–20) after transplantation (p = 0.003). This reduction was most prominent in 12 patients with SRBD, for whom the median AHI fell from 22 (range, 10–40) to 6.5 (range, 1–20; p = 0.010). SRBD improvement, defined as an AHI equal to or >50% and/or reduced to <10/h, was observed in eight of the 12 apneic patients. These results suggest that kidney transplantation may immediately improve SRBD in patients with ESRD. However, conclusions from this study should be taken with caution because of the limitations of our method, specifically the use of a portable recorder and a small number of patients.     

Rituximab treatment for posttransplant lymphoproliferative disorder (PTLD) induces complete remission of recurrent nephrotic syndrome

A 12-year-old Japanese boy who underwent kidney transplantation with a kidney from his mother developed severe proteinuria immediately after the operation. Because his original disease was nephrotic syndrome (focal segmental glomerulosclerosis, or FSGS) and electron microscopic examination of the renal biopsy showed foot process fusion, we diagnosed this as a recurrence of nephrotic syndrome to the transplanted kidney. Four months after the transplantation, posttransplant lymphoproliferative disorder (PTLD) developed, which was pathologically diagnosed as diffuse large B cell lymphoma. Treatment consisting of a reduction in immunosuppression resulted in improvement in PTLD a month after the start of treatment. However, relapse occurred 2 months after the first onset of PTLD, which we treated with rituximab (CD-20 monoclonal antibody 375 mg/m²) once weekly for a total of four doses. The PTLD resolved immediately after the rituximab treatment was started, and, interestingly, urinary protein levels also improved at the same time. Three years later, the boy shows no signs of PTLD, and no proteinuria has been detected. These findings suggest that rituximab may be an effective treatment for recurrence of nephrotic syndrome after transplantation and that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation.     

肾移植术后肿瘤(附22例报告)

目的探讨肾移植术后肿瘤发生情况和防治措施。方法对１９７８年６月～１９９８年５月行同种异体肾移植１６２４次／１５４７人术后肿瘤发生情况和免疫抑制剂使用进行回顾性分析。结果本组发现恶性肿瘤２２例,发生率为１４２％。分别发生于移植术后６个月～１０年,平均４８年。其中皮肤癌８例,肝右叶囊性腺癌１例,肝细胞癌２例,胃癌１例,直肠癌１例,结肠癌２例,回盲部腺癌１例,肾盂移行上皮癌２例,膀胱平滑肌肉瘤１例,肺恶性淋巴瘤１例,乳癌１例,口唇鳞癌１例。１６例行手术治疗,现存活１３例。６例属病变晚期,短期内死亡。结论肾移植术后免疫抑制剂的使用与肿瘤发生密切相关,应定期评估移植受者的免疫状态,早期发现肿瘤,并及时手术治疗,并减少免疫抑制剂用量。     

Lymphoproliferative disorder presenting as a tumor of the renal allograft

Post-transplant lymphoproliferative diseases (PTLDs) constitute a group of potentially life-threatening complications in solid organ transplantation, occurring in 1–2% of kidney transplant recipients. The absolute number of cases occurring at each transplant center remains small, making it difficult to assess incidence, prognosis, and treatment. We report a case of post-transplant lymphoproliferative disorder that developed in the allograft renal parenchyma 2 years after renal transplantation. This case implies that partial nephrectomy may be a safe and effective treatment protocol for renal lymphoma in allograft kidneys.     

Papillary microcarcinoma of the thyroid and secondary hyperparathyroidism in a patient on hemodialysis

Association between non-medullary thyroid carcinoma and secondary hyperparathyroidism have been rarely reported in patients with renal failure. A few cases of micropapillary thyroid carcinoma have been reported in patients before and after renal transplantation. We present a case of incidental detection of thyroid carcinoma at the time of parathyroidectomy in patient on dialysis after cadaver renal transplantation.     

Complete Atrioventricular Block After Kidney Transplantation in a Patient With Fabry Disease Receiving Enzyme Replacement Therapy: A Case Report

Fabry disease (FD) is a rare X-linked lysosomal storage disorder that results from the deficient activity of the lysosomal enzyme α-galactosidase A (α-Gal A) enzyme. Kidney transplantation is an option for treating end-stage renal disease in patients with FD. However, only a few cases of kidney transplantation have been reported involving patients with FD and end-stage renal disease and cardiomyopathy after enzyme replacement therapy. A 53-year-old man who underwent peritoneal dialysis was referred to our department because his brother was diagnosed with FD. The diagnosis of FD was also confirmed in our patient on account of the reduced leukocyte α-Gal A enzyme activity and mutation in the α-galactosidase A gene (p.Arg301Gln). Though our patient had end-stage renal disease, he received enzyme replacement therapy with 1 mg/kg agalsidase-β every 2 weeks (Fabrazyme; Genzyme Co, Mass, USA) owing to markedly diffuse cardiac hypertrophy. Six years later, he underwent successful deceased-donor kidney transplantation. The post-transplantation course was uneventful, 4 months after transplantation. However, though he showed T-cell-mediated rejection on kidney biopsy, lamellar lysosomal inclusions were not present in vascular endothelial cells. After several months, a permanent pacemaker was inserted owing to a complete atrioventricular block; the patient died of sepsis and candidemia 1 year later. Deceased-donor kidney transplantation was successfully performed in an FD patient with sustained enzyme replacement therapy. However, owing to high cardiac morbidity and infection risks even after enzyme replacement therapy, close monitoring of these risks is essential for increasing patient survival after kidney transplantation.     

Anticancer effect of sirolimus in renal allograft recipients with de novo malignancies

The inhibition of mTOR is a target for anticancer drugs in posttransplant malignancies. The influence of conversion to sirolimus after malignancy diagnosis was investigated on patient and renal allograft survivals. The 20 renal allograft recipients (4 women, 16 men) of ages 26 to 73 years (mean, 59 years) developed malignancies within 6 to 172 months (mean, 53 months) after transplantation. Three patients developed posttransplant lymphoproliferative disease (PTLD); four, Kaposi sarcoma, three, lung cancer; two, malignant melanoma; two, breast cancer; two, renal cell carcinoma; one, Merkel cell carcinoma; one, cutaneous T-cell lymphoma; one, larynx cancer; and one, gingival cancer. After tumor diagnosis, calcineurin inhibitors, azathioprine, or mycophenolate mofetil (MMF) were discontinued abruptly and sirolimus introduced (2 mg/d; target trough level, 4.0 to 8.0 ng/mL). Prednisone was maintained. The observation time of sirolimus therapy was 4 to 48 months (mean, 14 months). Two patients with PTLD (large B-cell lymphoma) and four with Kaposi sarcoma had full regressions. Eleven patients (larynx cancer, melanoma, breast cancer, T-cell lymphoma, renal cell carcinoma, Merkel cell carcinoma, and skin lymphoma) in addition to sirolimus therapy, underwent oncologic treatment, namely, surgery and/or chemotherapy. Six patients died from disseminated malignancy 4 to 9 months after conversion. One patient with T-cell lymphoma lost his graft; in the remaining patients, serum creatinine level was stable. In conclusion, Conversion to sirolimus resulted in regression of large B-cell lymphoma and Kaposi sarcoma. In patients with advanced or disseminated malignancy, the tumors progressed. Graft function was preserved after conversion to sirolimus.     

Hemorrhagic adenovirus cystitis after renal transplantation

PURPOSE: Viral infections are a major cause of postoperative morbidity and mortality after renal transplantation. Although cytomegalovirus, Epstein-Barr virus, and polyoma virus infections are common, there have been only a few reports of adenovirus infections. MATERIALS AND METHODS: We report an unusual case of a patient with adenovirus-induced hemorrhagic cystitis (AHC). We also performed a comprehensive MEDLINE review to identify similar cases. We then compared the presentation, management, and outcome of all patients to identify patterns that may facilitate the diagnosis and management of AHC. RESULTS: Review of the literature revealed 36 other reported cases of AHC in renal transplant recipients. Thirty-six of the 37 cases occurred within 1 year of transplantation. These patients presented with fever, dysuria, hematuria, and graft dysfunction. Thirty-four received high-dose steroids for treatment of symptoms of acute rejection. Four patients received antiviral medications. The infection was self-limited with mean duration of symptoms being 20 days. In all cases, serum creatinine returned to baseline or near baseline levels with resolution of symptoms. CONCLUSIONS: Although uncommon, AHC usually presents within 1 year of renal transplantation with a consistent constellation of symptoms. The infection appears to be self-limited with full recovery in most patients within 4 weeks. The efficacy of antiviral medications could not be determined in this review.