human
***task***
the task is to summarize an input biomedical literature in six sentences

***input***
the input is a biomedical literature

***output***
the output is the summary of an input biomedical literature in six sentences

***documentation***

***examples***

input: cytomegalovirus ( cmv ) disease can develop in up to 65 % of the patients without prophylaxis depending on the donor recipient constellation and is associated with an increased incidence of graft rejection and failure . in the high - risk constellation [ donor ( d ) + , recipient ( r ) ] pre - emptive therapy with antiviral drugs can substantially lower this percentage to around 20 % . however , low serum levels of or prolonged therapy with ganciclovir ( gcv ) may be associated with the development of gcv resistance in the presence of high levels of replicating virus . resistance to gcv primarily involves mutation of ul97 ( viral phosphotransferase ) or ul54 ( dna polymerase ) . with cidofovir and the foscarnet , apart from their high nephrotoxic potential , they act by inhibition of the viral dna polymerase similar to the gcv . so it is not surprising that recently cmv strains have been identified with resistance to all three of these drugs . here , we show that leflunomide may represent a treatment alternative for gcv - resistant cmv infection after renal transplantation in two patients . a 44 - year - old female patient with chronic renal failure due to sepsis and multiorgan failure during childbirth ( hellp - syndrome ) received her first cadaveric kidney transplant in 2005 ( high risk for cmv : d + , r ) . the patient was treated with cyclosporine ( csa ) , mycophenolate mofetil ( mmf ) and steroids , and received atg - fresenius induction therapy ( 4 mg / kg / day ) for 5 days . anti - rejection therapy consisted of steroid bolus over 3 days ( 250 mg methylprednisolone / day ) and a repeat course of atg - fresenius over 7 days . two months after the transplantation , cmv copies had been detected in the patient 's serum for the first time ( 736 copies / ml ) . viraemia could be controlled under repeat gcv treatment cycles for the following 6 months when suddenly 26000 copies / ml were measured . a short course of foscarnet was started . in the meantime , the resistance to gcv was confirmed by the presence of the ul97 mutation . due to the nephrotoxic effects of the foscarnet , the baseline creatinine had deteriorated from 2.4 to 3.3 mg / dl . two months later , the patient presented with a second relapse ( 5000 cmv copies / ml ) , and leflunomide was added to the patient 's immunosuppressive regimen . as recommended , the dosing was 100 mg / day of leflunomide for the first 4 days and 20 mg / day thereafter . during the subsequent course1 : the diagnosis of gcv - resistant cmv ( black arrow ) was made 220 days post - transplantation . the cmv burden increased to 25000 copies / ml and a short course of foscarnet ( grey box ) was administered . leflunomide has not been started until gcv - resistant cmv relapsed 2 months after the foscarnet . the patient remained virus free with impaired but stable renal function since then ( 800 days ) .2 : after detection of the gcv , resistance of the cmv ( black arrow ) leflunomide was started . in the first 10 days , insufficient trough levels were measured ( 30 g / ml ) and the cmv burden increased to 37000 copies / ml . a short course of foscarnet ( grey box ) was administered and trough levels of leflunomide were adjusted to 50100 g / ml . the patient was cleared of the virus and remained virus free with good renal function since then ( 280 days ) . a 63 - year - old female patient in chronic kidney failure due to glomerulonephritis received her first renal transplant in 1996 . the patient had then been diagnosed with a factor v leiden and apc resistance and put on continuous warfarin therapy . she was listed again and received her second renal transplant in september 2007 ( high risk for cmv : d + , r ) . the patient was immunized ( pra : 55 % ) and thus received an induction therapy consisting of basiliximab 20 mg on days 0 and 4 combined with atg - fresenius ( 4 mg / kg / day ) for 7 days according to our centre 's standard at that time . thirty days post - transplant , the cmv - pcr was positive for the first time ( 1550 copies / ml ) . under continuous oral valganciclovir ( vgcv ) , the cmv copies showed an undulating course until a 100 % increase was seen 3 months after the transplantation . under repeated i.v . gcv , the cmv copies almost tripled so that anti - cmv immunoglobulins were administered , and a cmv - resistance test revealed the presence of the ul97 mutation . the dosing was 80 mg / day for the first 4 days and 20 mg / day thereafter . under this treatmentthe trough levels did not reach therapeutical levels ( 30 g / ml ) . during the same time , the cmv copies increased further to 37000 / ml . after adjustment of the leflunomide doses and a short course of foscarnet , the cmv copies finally decreased to undetectable levels without relapse up until now . a 44 - year - old female patient with chronic renal failure due to sepsis and multiorgan failure during childbirth ( hellp - syndrome ) received her first cadaveric kidney transplant in 2005 ( high risk for cmv : d + , r ) . the patient was treated with cyclosporine ( csa ) , mycophenolate mofetil ( mmf ) and steroids , and received atg - fresenius induction therapy ( 4 mg / kg / day ) for 5 days . anti - rejection therapy consisted of steroid bolus over 3 days ( 250 mg methylprednisolone / day ) and a repeat course of atg - fresenius over 7 days . two months after the transplantation , cmv copies had been detected in the patient 's serum for the first time ( 736 copies / ml ) . viraemia could be controlled under repeat gcv treatment cycles for the following 6 months when suddenly 26000 copies / ml were measured . a short course of foscarnet was started . in the meantime , the resistance to gcv was confirmed by the presence of the ul97 mutation . due to the nephrotoxic effects of the foscarnet , the baseline creatinine had deteriorated from 2.4 to 3.3 mg / dl . two months later , the patient presented with a second relapse ( 5000 cmv copies / ml ) , and leflunomide was added to the patient 's immunosuppressive regimen . as recommended , the dosing was 100 mg / day of leflunomide for the first 4 days and 20 mg / day thereafter . during the subsequent course , the patients cmv viraemia disappeared within 6 weeks and remained undetectable since .1 : the diagnosis of gcv - resistant cmv ( black arrow ) was made 220 days post - transplantation . the cmv burden increased to 25000 copies / ml and a short course of foscarnet ( grey box ) was administered . leflunomide has not been started until gcv - resistant cmv relapsed 2 months after the foscarnet . the patient remained virus free with impaired but stable renal function since then ( 800 days ) .2 : after detection of the gcv , resistance of the cmv ( black arrow ) leflunomide was started . in the first 10 days , insufficient trough levels were measured ( 30 g / ml ) and the cmv burden increased to 37000 copies / ml . a short course of foscarnet ( grey box ) was administered and trough levels of leflunomide were adjusted to 50100 g / ml . the patient was cleared of the virus and remained virus free with good renal function since then ( 280 days ) . a 63 - year - old female patient in chronic kidney failure due to glomerulonephritis received her first renal transplant in 1996 . the patient had then been diagnosed with a factor v leiden and apc resistance and put on continuous warfarin therapy . she was listed again and received her second renal transplant in september 2007 ( high risk for cmv : d + , r ) . the patient was immunized ( pra : 55 % ) and thus received an induction therapy consisting of basiliximab 20 mg on days 0 and 4 combined with atg - fresenius ( 4 mg / kg / day ) for 7 days according to our centre 's standard at that time . thirty days post - transplant , the cmv - pcr was positive for the first time ( 1550 copies / ml ) . under continuous oral valganciclovir ( vgcv ) , the cmv copies showed an undulating course until a 100 % increase was seen 3 months after the transplantation . under repeated i.v . gcv , the cmv copies almost tripled so that anti - cmv immunoglobulins were administered , and a cmv - resistance test revealed the presence of the ul97 mutation . the dosing was 80 mg / day for the first 4 days and 20 mg / day thereafter . under this treatmentthe trough levels did not reach therapeutical levels ( 30 g / ml ) . during the same timeafter adjustment of the leflunomide doses and a short course of foscarnet , the cmv copies finally decreased to undetectable levels without relapse up until now . gcv - resistant cmv seems to develop preferably in those patients with a high - risk cmv constellation ( d + , r ) , a prolonged exposure of low levels of gcv and an intense immunosuppressive protocol . although antiviral agents are available to overcome this resistance , e.g. foscarnet , cidofovir and fomivirsen , their use is greatly limited by the overt nephrotoxic side effects . other possibilities include tapering of the immunosuppression , mtor - inhibitors , newer drugs and very high - dose - gcv . it seems to inhibit the intracellular formation of viral nucleocapsid and thus exert its antiviral effects completely differently to the other anti - cmv drugs . a prospective trial showed a successful course of 17 renal transplant patients with cmv disease treated with leflunomide . one case of a successful treatment of a multidrug - resistant cmv infection with leflunomide has been reported so far . here , a renal transplant patient developed cmv retinitis . in both our patients , foscarnet was administered so that a dual effect with the leflunomide can not be ruled out . in patient no .1 , leflunomide was not introduced until the cmv had relapsed 2 months after the administration of foscarnet .2 , insufficient leflunomide doses were given and the cmv viral load had increased further to very high levels . apart from adjusting the leflunomide dosage , we therefore decided to start a short course of foscarnet that helped eliminating the virus . in situations like this , a combination of the two drugs may be worthwhile : foscarnet to help reduce the virus burden quickly and leflunomide as a well - tolerated long - term prophylaxis .
output:

agent
cytomegalovirus ( cmv ) infection after renal transplantation is a problem of increasing concern resulting in significant morbidity and mortality . widespread use of ganciclovir ( gcv ) and valganciclovir ( vgcv ) may cause an increase of cmv resistance to these first line drugs . other treatment options are sparse and often complicated by adverse events , namely nephrotoxicity associated with foscarnet and cidofovir . leflunomide may be another treatment option for cmv infections . so far it is not clear if leflunomide can also be used in the case of gcv - resistant cmv infections . here we describe the use of leflunomide in two patients after renal transplantation with gcv - resistant cmv infections .
***task***
the task is to summarize an input biomedical literature in six sentences

***input***
the input is a biomedical literature

***output***
the output is the summary of an input biomedical literature in six sentences

***documentation***

***examples***

input: cytomegalovirus ( cmv ) disease can develop in up to 65 % of the patients without prophylaxis depending on the donor recipient constellation and is associated with an increased incidence of graft rejection and failure . in the high - risk constellation [ donor ( d ) + , recipient ( r ) ] pre - emptive therapy with antiviral drugs can substantially lower this percentage to around 20 % . however , low serum levels of or prolonged therapy with ganciclovir ( gcv ) may be associated with the development of gcv resistance in the presence of high levels of replicating virus . resistance to gcv primarily involves mutation of ul97 ( viral phosphotransferase ) or ul54 ( dna polymerase ) . with cidofovir and the foscarnet , apart from their high nephrotoxic potential , they act by inhibition of the viral dna polymerase similar to the gcv . so it is not surprising that recently cmv strains have been identified with resistance to all three of these drugs . here , we show that leflunomide may represent a treatment alternative for gcv - resistant cmv infection after renal transplantation in two patients . a 44 - year - old female patient with chronic renal failure due to sepsis and multiorgan failure during childbirth ( hellp - syndrome ) received her first cadaveric kidney transplant in 2005 ( high risk for cmv : d + , r ) . the patient was treated with cyclosporine ( csa ) , mycophenolate mofetil ( mmf ) and steroids , and received atg - fresenius induction therapy ( 4 mg / kg / day ) for 5 days . anti - rejection therapy consisted of steroid bolus over 3 days ( 250 mg methylprednisolone / day ) and a repeat course of atg - fresenius over 7 days . two months after the transplantation , cmv copies had been detected in the patient 's serum for the first time ( 736 copies / ml ) . viraemia could be controlled under repeat gcv treatment cycles for the following 6 months when suddenly 26000 copies / ml were measured . a short course of foscarnet was started . in the meantime , the resistance to gcv was confirmed by the presence of the ul97 mutation . due to the nephrotoxic effects of the foscarnet , the baseline creatinine had deteriorated from 2.4 to 3.3 mg / dl . two months later , the patient presented with a second relapse ( 5000 cmv copies / ml ) , and leflunomide was added to the patient 's immunosuppressive regimen . as recommended , the dosing was 100 mg / day of leflunomide for the first 4 days and 20 mg / day thereafter . during the subsequent course1 : the diagnosis of gcv - resistant cmv ( black arrow ) was made 220 days post - transplantation . the cmv burden increased to 25000 copies / ml and a short course of foscarnet ( grey box ) was administered . leflunomide has not been started until gcv - resistant cmv relapsed 2 months after the foscarnet . the patient remained virus free with impaired but stable renal function since then ( 800 days ) .2 : after detection of the gcv , resistance of the cmv ( black arrow ) leflunomide was started . in the first 10 days , insufficient trough levels were measured ( 30 g / ml ) and the cmv burden increased to 37000 copies / ml . a short course of foscarnet ( grey box ) was administered and trough levels of leflunomide were adjusted to 50100 g / ml . the patient was cleared of the virus and remained virus free with good renal function since then ( 280 days ) . a 63 - year - old female patient in chronic kidney failure due to glomerulonephritis received her first renal transplant in 1996 . the patient had then been diagnosed with a factor v leiden and apc resistance and put on continuous warfarin therapy . she was listed again and received her second renal transplant in september 2007 ( high risk for cmv : d + , r ) . the patient was immunized ( pra : 55 % ) and thus received an induction therapy consisting of basiliximab 20 mg on days 0 and 4 combined with atg - fresenius ( 4 mg / kg / day ) for 7 days according to our centre 's standard at that time . thirty days post - transplant , the cmv - pcr was positive for the first time ( 1550 copies / ml ) . under continuous oral valganciclovir ( vgcv ) , the cmv copies showed an undulating course until a 100 % increase was seen 3 months after the transplantation . under repeated i.v . gcv , the cmv copies almost tripled so that anti - cmv immunoglobulins were administered , and a cmv - resistance test revealed the presence of the ul97 mutation . the dosing was 80 mg / day for the first 4 days and 20 mg / day thereafter . under this treatmentthe trough levels did not reach therapeutical levels ( 30 g / ml ) . during the same time , the cmv copies increased further to 37000 / ml . after adjustment of the leflunomide doses and a short course of foscarnet , the cmv copies finally decreased to undetectable levels without relapse up until now . a 44 - year - old female patient with chronic renal failure due to sepsis and multiorgan failure during childbirth ( hellp - syndrome ) received her first cadaveric kidney transplant in 2005 ( high risk for cmv : d + , r ) . the patient was treated with cyclosporine ( csa ) , mycophenolate mofetil ( mmf ) and steroids , and received atg - fresenius induction therapy ( 4 mg / kg / day ) for 5 days . anti - rejection therapy consisted of steroid bolus over 3 days ( 250 mg methylprednisolone / day ) and a repeat course of atg - fresenius over 7 days . two months after the transplantation , cmv copies had been detected in the patient 's serum for the first time ( 736 copies / ml ) . viraemia could be controlled under repeat gcv treatment cycles for the following 6 months when suddenly 26000 copies / ml were measured . a short course of foscarnet was started . in the meantime , the resistance to gcv was confirmed by the presence of the ul97 mutation . due to the nephrotoxic effects of the foscarnet , the baseline creatinine had deteriorated from 2.4 to 3.3 mg / dl . two months later , the patient presented with a second relapse ( 5000 cmv copies / ml ) , and leflunomide was added to the patient 's immunosuppressive regimen . as recommended , the dosing was 100 mg / day of leflunomide for the first 4 days and 20 mg / day thereafter . during the subsequent course , the patients cmv viraemia disappeared within 6 weeks and remained undetectable since .1 : the diagnosis of gcv - resistant cmv ( black arrow ) was made 220 days post - transplantation . the cmv burden increased to 25000 copies / ml and a short course of foscarnet ( grey box ) was administered . leflunomide has not been started until gcv - resistant cmv relapsed 2 months after the foscarnet . the patient remained virus free with impaired but stable renal function since then ( 800 days ) .2 : after detection of the gcv , resistance of the cmv ( black arrow ) leflunomide was started . in the first 10 days , insufficient trough levels were measured ( 30 g / ml ) and the cmv burden increased to 37000 copies / ml . a short course of foscarnet ( grey box ) was administered and trough levels of leflunomide were adjusted to 50100 g / ml . the patient was cleared of the virus and remained virus free with good renal function since then ( 280 days ) . a 63 - year - old female patient in chronic kidney failure due to glomerulonephritis received her first renal transplant in 1996 . the patient had then been diagnosed with a factor v leiden and apc resistance and put on continuous warfarin therapy . she was listed again and received her second renal transplant in september 2007 ( high risk for cmv : d + , r ) . the patient was immunized ( pra : 55 % ) and thus received an induction therapy consisting of basiliximab 20 mg on days 0 and 4 combined with atg - fresenius ( 4 mg / kg / day ) for 7 days according to our centre 's standard at that time . thirty days post - transplant , the cmv - pcr was positive for the first time ( 1550 copies / ml ) . under continuous oral valganciclovir ( vgcv ) , the cmv copies showed an undulating course until a 100 % increase was seen 3 months after the transplantation . under repeated i.v . gcv , the cmv copies almost tripled so that anti - cmv immunoglobulins were administered , and a cmv - resistance test revealed the presence of the ul97 mutation . the dosing was 80 mg / day for the first 4 days and 20 mg / day thereafter . under this treatmentthe trough levels did not reach therapeutical levels ( 30 g / ml ) . during the same timeafter adjustment of the leflunomide doses and a short course of foscarnet , the cmv copies finally decreased to undetectable levels without relapse up until now . gcv - resistant cmv seems to develop preferably in those patients with a high - risk cmv constellation ( d + , r ) , a prolonged exposure of low levels of gcv and an intense immunosuppressive protocol . although antiviral agents are available to overcome this resistance , e.g. foscarnet , cidofovir and fomivirsen , their use is greatly limited by the overt nephrotoxic side effects . other possibilities include tapering of the immunosuppression , mtor - inhibitors , newer drugs and very high - dose - gcv . it seems to inhibit the intracellular formation of viral nucleocapsid and thus exert its antiviral effects completely differently to the other anti - cmv drugs . a prospective trial showed a successful course of 17 renal transplant patients with cmv disease treated with leflunomide . one case of a successful treatment of a multidrug - resistant cmv infection with leflunomide has been reported so far . here , a renal transplant patient developed cmv retinitis . in both our patients , foscarnet was administered so that a dual effect with the leflunomide can not be ruled out . in patient no .1 , leflunomide was not introduced until the cmv had relapsed 2 months after the administration of foscarnet .2 , insufficient leflunomide doses were given and the cmv viral load had increased further to very high levels . apart from adjusting the leflunomide dosage , we therefore decided to start a short course of foscarnet that helped eliminating the virus . in situations like this , a combination of the two drugs may be worthwhile : foscarnet to help reduce the virus burden quickly and leflunomide as a well - tolerated long - term prophylaxis .
output:
