Case Reports in Pediatrics

Case Reports in Pediatrics / 2014 / Article

Case Report | Open Access

Volume 2014 |Article ID 756819 | https://doi.org/10.1155/2014/756819

S. Stabouli, N. Printza, J. Dotis, A. Matis, D. Koliouskas, N. Gombakis, F. Papachristou, "Perilobar Nephroblastomatosis: Natural History and Management", Case Reports in Pediatrics, vol. 2014, Article ID 756819, 7 pages, 2014. https://doi.org/10.1155/2014/756819

Perilobar Nephroblastomatosis: Natural History and Management

Academic Editor: Denis A. Cozzi
Received14 May 2014
Accepted25 Jun 2014
Published09 Jul 2014

Abstract

Nephroblastomatosis (NB) has been considered as a precursor of Wilms tumor (WT). The natural history of NB seems to present significant variation as some lesions may regress spontaneously, while others may grow and expand or relapse and develop into WT later in childhood. Although, most investigators suggest adjutant chemotherapy, the effect and duration of treatment are not well established. Children with diffuse perilobar NB, Beckwith-Wiedemann syndrome, and hemihypertrophy seem to particularly benefit from treatment. We discuss our experience on two cases of NB and we review the literature for the management of this rare condition.

1. Introduction

Nephroblastomatosis (NB) defines the presence of diffuse or multiple nephrogenic rests (NRs). NRs are clusters of embryonic metanephric cells, which normally disappear after 36 weeks of gestational age. These lesions have been considered as precursors of Wilms tumor (WT). They can be present in about 1% of unselected infant kidneys at postmortem biopsies, while they are found in about 40% of kidneys with unilateral WTs and in nearly 100% of kidneys with bilateral WTs [1]. NB has also significant implications for the prognosis of pediatric patients with WTs, as its presence in the nontumoral part of the kidney may favor subsequent relapse of WTs [2].

NB can occur in any age, but it is most frequent in infants. NB in about of 40% of cases is bilateral, while unilateral presentation may be implicated with the presence of microscopic NRs on the contralateral kidney with increased risk of WT development. Limited publications have assessed the clinical course and the effect of management decisions on the outcome of children with NB. Most available data derive from small number of cases. In the current paper we discuss our experience on two cases of perilobar NB (PLNB) presented in our department with an interval of 20 years and we review challenging issues for the management of this rare condition.

2. Case Presentation

A 3.5-months-old girl was admitted to our department with right-sided hemihypertrophy. Screening with abdominal ultrasonography showed an enlarged right kidney with a large hypoechoic region presenting no corticomedullary differentiation as well as multifocal hypoechoic parenchymal foci bilaterally in both kidneys, suggesting PLNB. Magnetic Resonance Imaging (MRI) revealed multiple hypodense and nonenhancing cortical masses at both kidneys; the largest with a diameter of 2.65 cm was localized at the enlarged right kidney and presented reduced diffusion and faint enhancing tissue at periphery (Figures 1(a) and 1(b)). As all lesions were homogeneous without enhancement after contrast administration and a lenticular shape the diagnosis of PLNB was further suggested by the MRI findings. Spherical shape, heterogeneous, and enhancing nodules that would be suspicious for a WT were not present in the MRI. A second abdominal ultrasonography 2 months later showed enlargement of the already existing and new foci of NB bilaterally.

Some years ago we presented the case of a 23-month-old boy, who did not received any treatment for the initial diagnosis of right NB and developed WTs 24 and 42 months later at the left and the right kidney, respectively, despite regression of initial lesions of NB [3]. Review of the literature on the management of NB revealed one large retrospective study and several case reports describing in most cases adverse outcome in nontreated patients. Thus, our female patient initiated chemotherapy according to SIOP Wilms Tumor/2001 protocol and received vincristine and actinomycin D for 4 weeks. Abdominal ultrasonography at 4 weeks showed decrease of lesion’s size (shrinkage of the large right kidney mass volume from 7,56 cm3 to 3,26 cm3) and the patient received further cycles of vincristine and actinomycin D every 14 days for the next 3 months. Follow-up ultrasound at 4 months of treatment showed additional decrease of lesions dimensions (Figure 2). However, the follow-up period is currently too short to allow us to determine the response to treatment with confidence.

3. Discussion

In 1990 Beckwith et al. proposed the classification for NB into four categories: the perilobar (PLNB), intralobar (ILNB), combined, and universal [1]. All four categories have been associated with WT, PLNB with synchronous bilateral WTs, and ILNB with metachronous contralateral WTs. NRs and NB have been reported to have an increased frequency in several syndromes, including Beckwith-Wiedemann syndrome, hemihypertrophy, Perlman syndrome, and trisomy 18 [1, 4]. Nodular appearance may be more frequent in association with the presence of the above syndromes although diffuse pattern has also been reported [4, 5]. Pediatric patients with Beckwith-Wiedemann syndrome and idiopathic hemihypertrophy also have an increased risk, reported about 4%–10%, for developing embryonic tumors [4]. The clinical course of PLNB presents large variation; some lesions may grow and expand or decrease or fade and relapse later in childhood. The risk of developing one or more WTs during the natural history of disease is increased, especially in cases with diffuse hyperplastic PLNB (DHPLNB) [5]. DHPLNB presents as massive kidney enlargement due to thick ride of nephroblastic tissue. DHPLNB has also been associated with increased incidence of anaplastic WTs [5, 6].

As nephroblastomatosis is a preneoplastic condition, administration of chemotherapy could be considered under the concept of decreasing the volume of lesions and reducing the number of cells with malignant potential and subsequently the risk of malignant transformation [5, 7]. Treatment of NB with vincristine and actinomycin D is currently recommended as for stage 1 WT. However, chemotherapy may not be effective or prevent malignant transformation. Moreover, there are currently limited data in the literature to assess this issue with confidence.

Observation and close follow-up may be an option although epidemiologic evidence may not favor such decision. The main arguments in favor of nontreatment are the possible side effects of chemotherapy applied for nonmalignant condition, which has usually a favorable prognosis even when WT is developed. Moreover, chemotherapy may enhance the selection of resistant tumors [5, 7]. There are sporadic reported cases with spontaneous resolution of NB without treatment. However, the risk of developing WT seems to persist even years after initial diagnosis. Our male patient described above, who did not receive any treatment, presented spontaneous resolution of left kidney NB but developed new foci of NB and metachronous WT at the right kidney [3].

Forty-one individual cases have been published in the literature since 1978, of which 26 were after the classification from Beckwith et al. (Table 1) [725]. Observation of reported cases provides some evidence of the natural history of disease, but could not result in generalized conclusions about treatment decisions. Of nine with PLNB patients who received chemotherapy as initial treatment, seven developed WT at a mean of 29.9 months from diagnosis. Only one patient presented anaplastic pathology. All patients had a favorable outcome. Three patients did not receive any treatment; one of those suffering from PLNB developed WT, while the others have been followed up for a too short period. Ten cases of newborns with NB detected in postmortem biopsies were reported. The majority of these cases were associated with congenital abnormalities and died within the first days of life. In two cases, in which renal failure was a predominant feature, NB was found at biopsies performed after native nephrectomies during renal transplantation.


CaseReferenceAge at
diagnosis
SexDiagnosisClinical presentation at diagnosisCongenital defectsBiopsy
for NB
Ch for NB/
duration
Response to
initial Ch
Srg
For
NB
Ra
For
NB
Development
of WT
Outcome/
follow-up since initial diagnosis

1Gaulier et al., Pediatr Pathol., 1993 [8]NewbornUnilateral universal
NB
Cystic renal process discovered prenatallyYesYesNoYesNoNoAlive/1 yr

2Regalado et al., Pediatr Pathol.,1994 [9]NewbornMBilateral universal
NB
Potter's-like facies, hypoplastic lungs, ascites, and bilateral nephromegalyYesYes (postmortem)NoNoNoNoDead at age of
21 h

3 Verloes et al., Clin Genet., 1995 [10]Newborn Bilateral
NB
Fetal overgrowth, macroglossia, and ambiguous genitaliaYes/atypical Simpson-Golabi-Behmel and
Beckwith-Wiedemann S
Yes (postmortem)NoNoNoNoDead at age of 2 days

4Regalado et al., Pediatr Pathol Lab. Med., 1996 [11]NewbornMBilateral universal
NB
Prenatally diagnosed nephromegaly and renal failure NoYes (postmortem)NONoNoNoDOD at age of 3.5 mo

5Henneveld et al., Am J Med Genet., 1999 [12]8 moFUnilateral
NB
Nephromegaly FTH and other features of Perlman SYes/Perlman SYes (postmortem) NONoNoNoDead

6Spranger et al., J Clin Dysmorphol., 2001 [13]8 moMPeri- and intralobar
NB
Macrocephaly and short trunkYes/Ischiospinal dysostosis
with rib gaps
YesNONoNoNoAlive/2 mo

7Prasil et al., Med Pediatr Oncol., 2000 [7]15 moMBilateral
HPLN
Abdominal massNoYes 5 course VCR-AMD/20 wksPartial regressionNoNoYes/5 yrsAlive/5.5 yrs

8Prasil et al., Med Pediatr Oncol., 2000 [7]13 moMUnilateral
HPLN
Abdominal massNoYes3 course VCR-AMD/24 wksPartial regressionNoNoYes/28 moAlive/3.5 yrs

9Prasil et al., Med Pediatr Oncol., 2000 [7]3 yrsFBilateral
HPLN
Abdominal massNoYes2 course VCR-AMD/20 wksPartial regressionNONOYes, multifocal with anaplasia/18 moNED/4 yrs

10 Günther et al., Pediatr Radiol., 2004 [14]2 yrsFBilateral
DHPLN
NRNR NoNRNONOYes/12 moNR

11Cozzi et al., J Urol., 2004 [15]12 moFBilateral
HPLN
Abdominal massNoNo2-drug/NONOYes/4 wksNED/6 yrs

12Cozzi et al., J Urol., 2004 [15]13 moFUnilateral
HPLN
Abdominal mass/painNoNo2-drug/10 wksComplete regressionNONOYes/14 wksNED/32 mo

13Hu et al., Nephrol Dial Transplant., 2004 [16]21 moMBilateral
NB
Hypoplastic genitalia, glomerulopathy, and renal failureYes/atypical Denys-Drash S and
mutation of WT1 gene
Yes (nephrectomy at time of TN)NoNONONONR

14Hu et al., Nephrol Dial Transplant., 2004 [16]6 yrsMBilateral
NB
Pseudohermaphroditism, glomerulopathy, and renal failureYes/atypical Denys-drash S and
mutation of WT1 gene
Yes (nephrectomy at time of TN)NoNONONONR

15Christiansen et al., Pediatr Dev Pathol., 2005 [17]NewbornFBilateral
DHPLN
Congenital heart disease, anddiaphragmatic hernia Yes/mosaic duplication
1(q11q44)
Yes (postmortem)NoNONONODead at first day of life

16Machmouchi et al., Pediatr Nephrol., 2005 [18]8 moFBilateral
HPLN
Abdominal distention/respiratory distress/macroscopic hematuriaNoYesVRC-AMD-DX/24 wksPartial regressionNONONONED/1 yr

17
(sibl. of 18)
Gonzales et al., Am J Med Genet., 2005 [19]NewbornMBilateral
NB
Lumbosacral meningocele, large cystic and dysplastic kidneys, and oligohydramniosYes/diaphanospondylodysostosisYes (postmortem)NoNONONoDead at first day of life

18
(sibl. of 17)
Gonzales et al., Am J Med Genet., 2005 [19]NewbornFBilateral
NB
Oligohydramnios and cystic kidneysYes/diaphanospondylodysostosisYes (postmortem)NoNoNoNoDead at first day of life

19Traub et al., Virchows Arch., 2006 [20]Fetus 24 weeksMBilateral diffuse peri- and intralobar
NB
Yes/trisomy 13 and loss of WT1
expression
Yes (postmortem)NoNoNoNoDead at birth

20Witt et al., J Pediatr Hematol Oncol., 2009 [21]9 moFBilateral
DHPLN
Abdominal distention/respiratory distress/acquired von Willebrand diseaseYes/hip dysplasiaYes VCR-AMD/122 wks
13-cis retinoic acid/9 wks
VCR-AMD-DX/NR
Partial regressionNoNoYes/31.5 moAlive/3.6 yrs

21Vicens et al., Pediatr Dev Pathol., 2009 [22]1 yrMUnilateral
DHPLN
Abdominal massNo YesVCR-AMD/4 wksPartial regressionYesNoNoNR

22
(sibl. of 22)
Katzman et al., Pediatr Dev Pathol., 2009 [23]NewbornFCombined
NB
Prenatally diagnosed nephromegalyNoYes (postmortem)NoNoNoNoDOD at 6 day of life

23
(sibl. of 21)
Katzman et al., Pediatr Dev Pathol., 2009 [23]NewbornMIntralobar universal
NB
Prenatally diagnosed nephromegalyNoYes (postmortem)NoNoNoNoDOD at 10th day of life

24 Borny et al., JBR-BTR., 2009 [24]12 moFMultifocal
PLN
NRYes/Beckwith-Wiedemann SNRNRNRNRNRNRNR

25Sethi et al., Radiographics., 2010 [25]6 moFBilateral
DHPLN
Abdominal massNoNoNoNoNoYes/12 moAlive/NR

26Rauth et al., J Pediatr Surg., 2011 [26]10 moFBilateral
DHPLN
Urinary infectionNoNo2 courses of VCR-AMD/18 wks and 24 wksPartial regressionNoNoYes/3.5 yrsNR

Abbreviations: NB: nephroblastomatosis, Ch: chemotherapy, Srg: surgery, Ra: radiation, WT: Wilms tumor, f: female, m: male, sibl: sibling, HPRN: hyperplastic perilobar NB, DHPRN: diffuse hyperplastic perilobar NB, VRC: Vincristine, AMD: dactinomycin, DX: doxorubicin, NR: not reported, DOD: dead of disease, NED: no evidence of disease, TN: transplantation.

One large series of 52 patients provides data on patients with long-term survival of HPLNB [5]. The patients were followed up for at least 5 years. The lesions were bilateral in 49/52 cases, 45/52 had DHPLNB, and 8/52 patients had features of Beckwith-Wiedemann or other syndromes. Only three patients were observed without receiving chemotherapy at diagnosis. All three developed WT subsequently at 4 and 10 months later. Similar was the clinical course in our first case, as described earlier. Of the remaining 49 patients who received chemotherapy all presented an initial decrease in lesions volume. However, 55% of those that received only chemotherapy developed WT, while among patients who were treated with nephrectomy and chemotherapy 19% (three patients) developed WT. Chemotherapy seems to delay the occurrence of WT in patients with HPLNB. In the study by Perlman et al., the mean time from initial diagnosis of HPRNB to the appearance of WT was 35 months in treated pediatric patients (range of 12–60 months) compared to mean of 6.5 months in those who did not receive treatment. Similarly in cases in Table 1, WT developed in shorter time period if chemotherapy was administrated (35 months versus 12 months in the nontreated patients). Even if the patient develops WT during treatment the delay of appearance may allow nephron-sparing approaches.

Another interesting issue concerning the clinical course of PLNB is that the speed of the response to chemotherapy, which may suggest the duration of chemotherapy, presented significant variation among reported cases. In many cases prolonged chemotherapy is required to achieve regression of disease [5]. These observations may suggest that the duration of chemotherapy in children with PLNB needs to be continuously assessed during follow-up and treatment. DHPLNB may represent increased burden of disease. Moreover, in the cohort described by Perlman et al., children who presented relapses with new lesions during chemotherapy and children with genetic syndromes had an increased risk for WT. These children may need prolonged treatment. In the case of our female patient the cluster of unfavorable prognostic factors including hemihypertrophy and transient initial response to treatment reinforce the decision for chemotherapeutic treatment. Genetic analysis for mutations in WT1, WT2, and WTX genes may further guide the duration and the intensity of chemotherapeutic schemes. An ongoing trial on the effect of chemotherapy in preserving renal units in children with DHPLNB and preventing WT development may give guidance for the management of disease [6]. Patients will initially receive vincristine and actinomycin D and maybe partial nephrectomy after initial chemotherapy, especially if there is no response or if there is progression of disease or development of new lesions during therapy.

In conclusion, chemotherapy maybe the optimal treatment decision for pediatric patients with PLNB. Current evidence favor the individualization of treatment and close follow-up of the children with PLNB as suggested for individuals with increased risk for WT [6]. Patients should be followed up by imaging at a maximum interval of 3 months for a minimum of 7 years, as early detection of a WT may be critical for patient and kidney survival.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. J. B. Beckwith, N. B. Kiviat, and J. F. Bonadio, “Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms' tumor,” Pediatric Pathology, vol. 10, no. 1-2, pp. 1–36, 1990. View at: Publisher Site | Google Scholar
  2. C. Bergeron, C. Iliescu, P. Thiesse et al., “Does nephroblastomatosis influence the natural history and relapse rate in Wilms' tumour? A single centre experience over 11 years,” European Journal of Cancer, vol. 37, no. 3, pp. 385–391, 2001. View at: Publisher Site | Google Scholar
  3. F. Papadopoulou, S. C. Efremidis, N. Gombakis, J. Tsouris, and T. Kehagia, “Nephroblastomatosis: the whole spectrum of abnormalities in one case,” Pediatric Radiology, vol. 22, no. 8, pp. 598–599, 1992. View at: Publisher Site | Google Scholar
  4. P. L. Choyke, M. J. Siegel, A. W. Craft et al., “Screening for Wilms tumor in children with Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy,” Medical and Pediatric Oncology, vol. 32, no. 3, pp. 196–200, 1999. View at: Publisher Site | Google Scholar
  5. E. J. Perlman, P. Faria, A. Soares et al., “Hyperplastic perilobar nephroblastomatosis: long-term survival of 52 patients,” Pediatric Blood and Cancer, vol. 46, no. 2, pp. 203–221, 2006. View at: Publisher Site | Google Scholar
  6. E. J. Perlman, “Pediatric renal tumors: practical updates for the pathologist,” Pediatric and Developmental Pathology, vol. 8, no. 3, pp. 320–338, 2005. View at: Publisher Site | Google Scholar
  7. P. Prasil, J. M. Laberge, M. Bond et al., “Management decisions in children with nephroblastomatosis,” Medical and Pediatric Oncology, vol. 35, no. 4, pp. 429–432, 2000. View at: Google Scholar
  8. A. Gaulier, L. Boccon-Gibod, P. Sabatier, and G. Lucas, “Panlobar nephroblastomatosis with cystic dysplasia: an unusual case with diffuse renal involvement studied by immunohistochemistry,” Pediatric Pathology, vol. 13, no. 6, pp. 741–749, 1993. View at: Publisher Site | Google Scholar
  9. J. J. Regalado, M. M. Rodriguez, J. H. Bruce, and J. B. Beckwith, “Bilateral hyperplastic nephromegaly, nephroblastomatosis, and renal dysplasia in a newborn: a variety of universal nephroblastomatosis,” Pediatric Pathology, vol. 14, no. 3, pp. 421–432, 1994. View at: Publisher Site | Google Scholar
  10. A. Verloes, B. Massart, I. Dehalleux, J. P. Langhendries, and L. Koulischer, “Clinical overlap of Beckwith-Wiedemann, Perlman and Simpson-Golabi-Behmel syndromes: a diagnostic pitfall,” Clinical Genetics, vol. 47, no. 5, pp. 257–262, 1995. View at: Google Scholar
  11. J. J. Regalado, M. M. Rodriguez, and J. B. Beckwith, “Multinodular hyperplastic pannephric nephroblastomatosis with tubular differentiation: a new morphologic variant,” Pediatric Pathology and Laboratory Medicine, vol. 16, no. 6, pp. 961–972, 1996. View at: Publisher Site | Google Scholar
  12. H. T. Henneveld, R. A. van Lingen, B. C. Hamel, I. Stolte-Dijkstra, and A. J. van Essen, “Perlman syndrome: four additional cases and review,” American Journal of Medical Genetics, vol. 86, no. 5, pp. 439–446, 1999. View at: Google Scholar
  13. J. Spranger, S. Self, K. B. Clarkson, and G. S. Pai, “Ischiospinal dysostosis with rib gaps and nephroblastomatosis,” Clinical Dysmorphology, vol. 10, no. 1, pp. 19–23, 2001. View at: Publisher Site | Google Scholar
  14. P. Günther, J. Tröger, N. Graf, K. L. Waag, and J. P. Schenk, “MR volumetric analysis of the course of nephroblastomatosis under chemotherapy in childhood,” Pediatric Radiology, vol. 34, no. 8, pp. 660–664, 2004. View at: Publisher Site | Google Scholar
  15. F. Cozzi, A. Schiavetti, D. A. Cozzi et al., “Conservative management of hyperplastic and multicentric nephroblastomatosis,” Journal of Urology, vol. 172, no. 3, pp. 1066–1069, 2004. View at: Publisher Site | Google Scholar
  16. M. Hu, G. Y. Zhang, S. Arbuckle et al., “Prophylactic bilateral nephrectomies in two paediatric patients with missense mutations in the WT1 gene,” Nephrology Dialysis Transplantation, vol. 19, no. 1, pp. 223–226, 2004. View at: Publisher Site | Google Scholar
  17. L. R. Christiansen, J. M. Lage, D. J. Wolff, G. S. Pai, and R. A. Harley, “Mosaic duplication 1(q11q44) in an infant with nephroblastomatosis and mineralization of extraplacental membranes,” Pediatric and Developmental Pathology, vol. 8, no. 1, pp. 115–123, 2005. View at: Publisher Site | Google Scholar
  18. M. Machmouchi, M. Bayoumi, I. Mamoun, K. Al-Ahmadi, and H. Kanaan, “Bilateral universal nephroblastomatosis in an 8-month-old infant treated with chemotherapy,” Pediatric Nephrology, vol. 20, no. 7, pp. 1007–1010, 2005. View at: Publisher Site | Google Scholar
  19. M. Gonzales, A. Verloes, M. H. Saint Frison et al., “Diaphanospondylodysostosis (DSD): confirmation of a recessive disorder with abnormal vertebral ossification and nephroblastomatosis,” The American Journal of Medical Genetics, vol. 136, no. 4, pp. 373–376, 2005. View at: Publisher Site | Google Scholar
  20. F. Traub, K. Sickmann, M. Tessema, L. Wilkens, H. H. Kreipe, and K. Kamino, “Nephroblastomatosis and loss of WT1 expression associated with trisomy 13,” Virchows Archiv, vol. 448, no. 2, pp. 214–217, 2006. View at: Publisher Site | Google Scholar
  21. O. Witt, S. Hämmerling, C. Stockklausner et al., “13- cis retinoic acid treatment of a patient with chemotherapy refractory nephroblastomatosis,” Journal of Pediatric Hematology/Oncology, vol. 31, no. 4, pp. 296–299, 2009. View at: Publisher Site | Google Scholar
  22. J. Vicens, A. Iotti, M. G. Lombardi, R. Iotti, and M. T. G. De Davila, “Diffuse hyperplastic perilobar nephroblastomatosis,” Pediatric and Developmental Pathology, vol. 12, no. 3, pp. 237–238, 2009. View at: Publisher Site | Google Scholar
  23. P. J. Katzman, G. L. Arnold, E. C. Lagoe, and V. Huff, “Universal nephroblastomatosis with bilateral hyperplastic nephromegaly in siblings,” Pediatric and Developmental Pathology, vol. 12, no. 1, pp. 47–52, 2009. View at: Publisher Site | Google Scholar
  24. E. Borny, B. Mortelé, and P. Seynaeve, “Multifocal nephroblastomatosis in beckwith-wiedemann syndrome,” JBR-BTR, vol. 92, no. 3, pp. 144–145, 2009. View at: Google Scholar
  25. A. T. Sethi, L. D. Narla, S. J. Fitch, and W. J. Frable, “Wilms tumor in the setting of bilateral nephroblastomatosis,” Radiographics, vol. 30, no. 5, pp. 1421–1425, 2010. View at: Publisher Site | Google Scholar
  26. T. P. Rauth, J. Slone, G. Crane, H. Correa, D. L. Friedman, and H. N. Lovvorn III, “Laparoscopic nephron-sparing resection of synchronous Wilms tumors in a case of hyperplastic perilobar nephroblastomatosis,” Journal of Pediatric Surgery, vol. 46, no. 5, pp. 983–988, 2011. View at: Publisher Site | Google Scholar

Copyright © 2014 S. Stabouli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views4676
Downloads977
Citations

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.