hemolytic uremic syndrome ( hus ) is characterized by the triad of microangiopathic hemolytic anemia , thrombocytopenia and acute renal failure .
hus in children is most commonly caused by shiga - like toxin - producing escherichia coli ( stec ) , with pneumococcal - associated hus ( phus ) accounting for 5% of acquired cases .
up to 85% of patients require dialysis with a mortality rate of > 10% [ 1 , 2 ] .
streptococcus pneumoniae cleaves n - acetylneuraminic acid ( sialic acid ) and exposes the thomsen  friedenreich antigen ( t - antigen ) on glomerular endothelial cell glycoproteins .
this process , known as t - activation , then leads to igm binding from circulating igm anti - t antibodies , and the clinical syndrome of hus ( figure  1 ) . 

if necessary , transfusion of washed blood products is preferable to avoid increasing the levels of preformed anti - t antibodies , which are high in unwashed products .
anecdotal evidence supports the use of plasma exchange with 5% albumin replacement , and avoiding fresh frozen plasma ( ffp ) due to preformed anti - t antibodies in the pooled product [ 57 ] .
a 12-year - old female with steroid - resistant nephrotic syndrome presented to the emergency department with fever , shortness of breath and cough .
she was started on vancomycin and cefotaxime , and admitted to our pediatric intensive care unit for further management .
past medical history was remarkable for the diagnosis of nephrotic syndrome at the age of 5 years .
although initially responsive to steroids she suffered several relapses when the steroid dose was tapered . at the age of 6 years
genetic testing for inherited nephrotic syndromes identified a heterozygous , non - coding mutation in the transient receptor potential cation channel subfamily c member 6 ( trpc6 ) gene of unknown clinical significance .
after relapse and a failed attempt to induce full remission with oral steroids she was started on tacrolimus . over the next 3 years she had a partial clinical response , with improved edema but persistent proteinuria .
out of concern for missed focal segmental glomerular sclerosis ( fsgs ) and long - term calcineurin inhibitor nephrotoxicity , a repeat biopsy was performed .
due to drug - resistant nephrotic syndrome and biopsy findings suggesting possible drug injury she was started on a trial of adrenocorticotrophic hormone ( h.p .
acthar gel ; mallinckrodt pharmaceuticals , st louis , mo , usa ) twice weekly in addition to tacrolimus .
an initial blood culture grew out s. pneumoniae at 8 h , and a nasopharyngeal swab pcr was positive for parainfluenza type 2 . overnight the patient developed oliguria , the creatinine increased from 1.4 to 2.4 mg / dl , and the hemoglobin decreased from 11.4 to 7.4 g / dl ( table  1 ) .
she was transfused one unit of unwashed packed red blood cells ( prbcs ) and started on continuous veno - venous hemodiafiltration due to worsening kidney function and pulmonary edema . 

table  1.pertinent laboratory datalaboratory testadmission ( day 1)after plex ( day 8)day 25referencehemoglobin ( g / dl)7.48.610.112.115.1hematocrit ( % ) 22.626.429.536.144.3platelet count ( 109/l)10081225140440lactate dehydrogenase ( u / l)294nana100250bilirubin ( mg / dl)0.10.9na00.4blood urea nitrogen ( mg / dl)3010509.018.0creatinine ( mg / dl)1.41.980.20.8fibrinogen ( mg / dl)737426na177401pt / aptt ( in seconds)19.4/48.621.1/43.9na1216.1/2340.6dctnanegativepositivenegativeadamst1372%70%smear ( schistocytes)positivenegativeadamst13 , a disintegrin and metalloproteinase with thrombospondin type 1 motif , member 13 ; dct , direct coombs test ; na , not available / not obtained ; plex , plasma exchange ; pt / aptt , prothrombin time / activated partial thromboplastin time .
pertinent laboratory data adamst13 , a disintegrin and metalloproteinase with thrombospondin type 1 motif , member 13 ; dct , direct coombs test ; na , not available / not obtained ; plex , plasma exchange ; pt / aptt , prothrombin time / activated partial thromboplastin time . on hospital
a computed tomography scan of the chest demonstrated bilateral patchy consolidation consistent with bronchopneumonia , and bilateral pleural effusions .
high - dose hydrocortisone was administered due to concern for adrenal suppression from chronic steroid / acthar administration .
the platelet count continued to decrease and her clinical condition worsened , requiring intravenous vasoactive support .
initially the presumed mechanism for her worsening clinical course was the development of thrombocytopenia - associated multiple organ failure ; therefore , ffp was used as the replacement fluid during the exchange .
the possibility of phus was raised shortly after initiation of plex and the lack of clinical response to replacement with ffp .
a direct coombs test was checked and came back negative ; however , a false negative could be explained by the removal of plasma antibodies from plex . indeed , a follow - up direct coombs test drawn after completion of plex was positive .
the platelet count reached a nadir of 36 on day 13 , after which it slowly improved without the need for transfusion . with supportive care , antibiotics and temporary kidney replacement therapy ( krt ) , the patient slowly recovered .
she was eventually discharged home on hospital day 39 , her creatinine having returned to the baseline level of 0.6 mg / dl .
an initial blood culture grew out s. pneumoniae at 8 h , and a nasopharyngeal swab pcr was positive for parainfluenza type 2 . overnight the patient developed oliguria , the creatinine increased from 1.4 to 2.4 mg / dl , and the hemoglobin decreased from 11.4 to 7.4 g / dl ( table  1 ) .
she was transfused one unit of unwashed packed red blood cells ( prbcs ) and started on continuous veno - venous hemodiafiltration due to worsening kidney function and pulmonary edema . 

table  1.pertinent laboratory datalaboratory testadmission ( day 1)after plex ( day 8)day 25referencehemoglobin ( g / dl)7.48.610.112.115.1hematocrit ( % ) 22.626.429.536.144.3platelet count ( 109/l)10081225140440lactate dehydrogenase ( u / l)294nana100250bilirubin ( mg / dl)0.10.9na00.4blood urea nitrogen ( mg / dl)3010509.018.0creatinine ( mg / dl)1.41.980.20.8fibrinogen ( mg / dl)737426na177401pt / aptt ( in seconds)19.4/48.621.1/43.9na1216.1/2340.6dctnanegativepositivenegativeadamst1372%70%smear ( schistocytes)positivenegativeadamst13 , a disintegrin and metalloproteinase with thrombospondin type 1 motif , member 13 ; dct , direct coombs test ; na , not available / not obtained ; plex , plasma exchange ; pt / aptt , prothrombin time / activated partial thromboplastin time .
pertinent laboratory data adamst13 , a disintegrin and metalloproteinase with thrombospondin type 1 motif , member 13 ; dct , direct coombs test ; na , not available / not obtained ; plex , plasma exchange ; pt / aptt , prothrombin time / activated partial thromboplastin time . on hospital
a computed tomography scan of the chest demonstrated bilateral patchy consolidation consistent with bronchopneumonia , and bilateral pleural effusions .
high - dose hydrocortisone was administered due to concern for adrenal suppression from chronic steroid / acthar administration .
the platelet count continued to decrease and her clinical condition worsened , requiring intravenous vasoactive support .
initially the presumed mechanism for her worsening clinical course was the development of thrombocytopenia - associated multiple organ failure ; therefore , ffp was used as the replacement fluid during the exchange .
the possibility of phus was raised shortly after initiation of plex and the lack of clinical response to replacement with ffp .
a direct coombs test was checked and came back negative ; however , a false negative could be explained by the removal of plasma antibodies from plex .
indeed , a follow - up direct coombs test drawn after completion of plex was positive .
the platelet count reached a nadir of 36 on day 13 , after which it slowly improved without the need for transfusion . with supportive care , antibiotics and temporary kidney replacement therapy ( krt ) , the patient slowly recovered .
she was eventually discharged home on hospital day 39 , her creatinine having returned to the baseline level of 0.6 mg / dl .
diagnosis of phus is based on the association of the clinical triad of hus with confirmed or suspected s. pneumoniae infection .
evidence of t - antigen exposure ( direct coombs test , polyagglutination test or peanut lectin agglutination test ) can help support the diagnosis , but is not mandatory .
the patient met diagnostic criteria for phus , and additionally had a positive direct coombs test ( table  1 ) .
while disseminated intravascular coagulation ( dic ) with multiorgan failure was considered as an alternative diagnosis , it was eventually rejected due to evidence of autoimmune hemolysis ( schistocytes , positive coombs ) , and normal fibrinogen level .
initially the mildly prolonged prothrombin time / activated partial thromboplastin time ( pt / aptt ) hinted toward the possibility of dic , but coagulation abnormalities are common in phus , and dic is typically not considered without significant pt / aptt elongation along with decreased fibrinogen .
the median age of phus reported in the literature ranges from 13 to 24 months [ 1 , 13 , 14 ] .
two of these patients had undergone splenectomy , and so underlying immunodeficiency is presumably a risk factor for development of phus at an older age .
nephrotic syndrome is a well - known cause of secondary immunodeficiency due to multiple factors including edema , urinary loss of immunoglobulins and complement factors , and secondary effects of cytotoxic therapies [ 1921 ] .
streptococcus pneumoniae in particular is a major cause of sepsis and peritonitis in nephrotic syndrome , yet this is the first reported case of phus in a patient with nephrotic syndrome .
tacrolimus has a well - known association with hus , but does not typically cause a positive coombs test .
also , in a review of 16 cases of tacrolimus - induced hus , the average time from initiating tacrolimus to disease onset was 7.1 months , while our patient had been treated for over 3 years .
in addition to tacrolimus , our patient was started on acthar 2 months prior to presentation .
acthar gel is a repository corticotropin injection that was first approved by the fda in 1952 for a variety of autoimmune and inflammatory diseases , and is an approved treatment for nephrotic syndrome .
proposed mechanisms of action include increased endogenous steroidogenesis , immunomodulation via melanocortin receptor binding and podocyte protection .
adrenocorticotropic hormone ( acth ) therapy is tolerated by most patients , with adverse effects similar to those of glucocorticoid therapy ( weight gain , bone loss , cushingoid features ) .
although we do not suspect a pathogenic role of acth in the development of hus , and our patient had several risk factors for pneumococcal infection , it is worth noting this serious complication in the setting of acthar administration .
the clinical course of phus is typically more severe than diarrheal hus , with more frequent need for dialysis and transfusions , and longer hospital stays . in 2008 ,
copelovitch and kaplan reviewed all previous cases of phus reported in the english literature , and found a 12.3% mortality rate , with 10% progressing to end - stage renal disease , and 16% with chronic kidney disease and/or hypertension .
management of phus is primarily supportive , with prompt administration of antibiotics , transfusions and krt as needed .
ffp and unwashed prbcs should be avoided , due to the possibility of increased exposure to anti - t antigen igm antibodies .
plasma exchange with 5% albumin replacement fluid has been advocated for the treatment of phus due to the theoretical benefit of removing anti - t igm antibodies and bacterial neuraminidase .
guidelines rate the indication for plasma exchange as a category iii : optimum role of apheresis therapy is not established and care should be individualized .
further conclusions can not be reached without a randomized controlled trial or high - powered case series .
the advisory committee on immunization practices recommends that children aged 618 years with immunocompromising conditions ( including nephrotic syndrome ) receive both the 13-valent pneumococcal conjugate vaccine ( pcv13 ) and the 23-valent pneumococcal polysaccharide vaccine ( ppsv23 ) ( table  2 ) . the epidemiology of invasive pneumococcal disease , and phus in particular , has been altered dramatically with the introduction of pneumococcal vaccines .
most notably , rates of invasive pneumococcal disease have plummeted in children younger than 5 years , and non - vaccine serotypes have risen in prevalence .
the patient received pcv7 vaccination from her primary pediatrician , but did not receive subsequent pcv13 or ppsv23 .
results of serotyping for this case are still pending , but the possibility that the infection was caused by a vaccine - preventable serotype underscores the importance of ensuring vaccine understanding among both community and specialist pediatricians . 
 table  2.pneumococcal immunization recommendations in nephrotic syndromeacip recommendations for pcv13 and ppsv23 administration in children aged 618 years old with immunocompromising conditions ( including nephrotic syndrome)pcv13ppsv23ppsv23patients who have not previously received ppsv231 dose1st dose 8 weeks after pcv13 dose2nd dose 5 years after 1st ppsv23 dosepatients who have previously received ppsv231 dose 8 weeks after last ppsv23 dosen / a  already received 1st dose5 years after 1st ppsv23 doseacip , advisory committee on immunization practices ; pcv13 , 13-valent pneumococcal conjugate vaccine ; ppsv23 , 23-valent pneumococcal polysaccharide vaccine .
pneumococcal immunization recommendations in nephrotic syndrome acip , advisory committee on immunization practices ; pcv13 , 13-valent pneumococcal conjugate vaccine ; ppsv23 , 23-valent pneumococcal polysaccharide vaccine .
this case highlights the diagnostic challenges that phus presents , and the importance of early recognition .
management often requires intensive supportive care with dialysis , transfusion with washed blood products and consideration of plex with 5% albumin .
this case also highlights the need to consider phus in older patients with immunocompromising conditions such as nephrotic syndrome that increase the risk of invasive pneumococcal infection
. finally , proper vaccination practices are important to help prevent pneumococcal disease and its associated sequelae .
 pneumococcal - associated hemolytic uremic syndrome ( phus ) is a rare but severe complication of invasive streptococcus pneumoniae infection . 
 we report the case of a 12-year - old female with steroid - resistant nephrotic syndrome treated with adrenocorticotrophic hormone ( h.p . 
 acthar gel ) , who developed pneumococcal pneumonia and subsequent phus . 
 while nephrotic syndrome is a well - known risk factor for invasive pneumococcal disease , this is the first reported case of phus in an adolescent patient with nephrotic syndrome , and reveals novel challenges in the diagnosis , treatment and potential prevention of this complication . 
Background
Case report
In the intensive care unit
Discussion
Conflict of interest statement