ARTICLE

An Overview of Pediatric Hemolytic

Uremic Syndrome
Milena Fraustro, MD, Melissa Clemente, MD
Nicklaus Children’s Hospital, Miami, Florida

EDUCATION GAP AUTHOR DISCLOSURE: Drs Fraustro and

Clemente have disclosed no financial
relationships relevant to this article. This
Hemolytic uremic syndrome (HUS) is one of the main causes of community-
commentary does not contain a
acquired acute kidney injury (AKI). AKI is responsible for significant morbidity discussion of an unapproved/
and mortality in the pediatric population. Pediatricians must understand the investigative use of a commercial
new nomenclature of HUS as well as recognize the different signs and symp- product/device.

toms of this entity to initiate prompt treatment.

ABBREVIATIONS

OBJECTIVES After completing this article, readers should be able to

ADAMTS13 a disintegrin and
metalloproteinase with a
thrombospondin type 1
1. Identify the signs and symptoms of HUS. motif, member 13
AKI acute kidney injury
2. Discuss the initial evaluation and management of suspected HUS. C3 complement 3
C4 complement 4
3. Describe the updated terminology for classifying HUS.
CFB complement factor B
4. Make pertinent subspecialty referrals to support patients with HUS. CFI complement factor I
CHF complement factor H
5. Discuss the prognosis of HUS. DAT direct antiglobulin test
DGKε diacylglycerol kinase ε
DIC disseminated intravascular
CASE coagulation
GB3 globotriaosylceramide-3
A previously healthy 4-year-old girl with incomplete vaccinations presented for an HUS hemolytic uremic syndrome
evaluation of 5 days of fever (T-max 39 °C), severe cough, increased work breathing, LDH lactate dehydrogenase
MAC membrane attack complex
and chest and back pain. Laboratory analysis revealed a white blood cell count of
MAHA microangiopathic hemolytic
10.4 10K/μL, anemia with a hemoglobin of 9.2 g/dL, thrombocytopenia with a plate- anemia
let count of 12 610 K/μL, C-reactive protein of 38.9 mg/dL, and procalcitonin of MCP membrane-cofactor protein
440 ng/mL. Coagulation studies were abnormal, with a prothrombin time (PT) PT prothrombin time
PTT partial thromboplastin time
of 19.3 seconds (nl 11.6–15.4 seconds), partial thromboplastin time (PTT) of 65.3 sec- SC5b-9 soluble terminal
onds (nl 22.8–38.2 seconds), and fibrinogen of 1055 mg/dL. Renal function was nor- complement complex
mal. A chest radiograph demonstrated a near-complete whiteout of the right enzyme
S. pneumoniae Streptococcus pneumoniae
hemithorax with a pleural effusion. Such findings were confirmed by an ultrasound
STEC Shiga toxin–producing
and computed tomography scan, which showed necrotizing pneumonia with a sig- Escherichia coli
nificantly large complex pleural effusion. A blood culture was obtained, and the TF antigen Thomsen-Friedenreich
TMA thrombotic
patient was started on broad-spectrum antibiotics for pneumonia. Soon after admis-
microangiopathy antigen
sion, the patient decompensated with worsening respiratory distress, decreased TTP thrombotic
urine output with a 3-L positive fluid balance, and hypertension. Repeat laboratory thrombocytopenic
studies showed worsening anemia with a hemoglobin of 8.7 g/dL and worsening purpura
US ultrasound
thrombocytopenia with a platelet count of 2110 K/μL. Additional tests to check WBC white blood cell count
for hemolysis demonstrated a lactate dehydrogenase (LDH) of 5589 IU/L, uric acid

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by Tomas Krepostman
 of 6.3 mg/dL, haptoglobin of <20 mg/dL, a Coombs-positive referred to as typical HUS. All other causes of HUS were
result, and the presence of schistocytes identified on a blood referred to as atypical HUS. Often, children with atypical
smear. The patient also developed intrarenal acute kidney HUS had persistent or recurrent disease, and some had a
injury (AKI) with a creatinine of 1.37 mg/dL and blood urea family history of HUS. These observations contributed to sig-
nitrogen of 62 mg/dL and required hemodialysis. The nificant advances in the understanding of the etiology and
patient was in multiorgan failure; she was intubated and pathophysiology of HUS, particularly the role of the alterna-
started on mechanical respiratory support. A chest tube tive complement pathway. The terminology for HUS is con-
was placed, and pleural fluid cultures were positive for stantly evolving as our understanding of its pathophysiology
Streptococcus pneumoniae. Stool culture was negative for improves (Figure 1). HUS should be referred to as primary or
Shiga toxin–producing Escherichia coli (STEC). Further stud- secondary HUS based on the pathophysiology. Primary
ies showed low complement levels: C3 level of 49.2 mg/dL HUS, formerly referred to as atypical, is a disorder of comple-
(92–184 mg/dL), C4 level of 4.5 mg/dL (20–59 mg/dL), ment regulation due to an underlying genetic predisposition.
elevated soluble terminal complement complex enzyme Secondary HUS, formerly referred to as typical, is caused by
(SC5b-9) of 1415 ng/mL (normal <244 ng/mL), and normal an internal or external event (infection, malignancy, trans-
“a thrombospondin type 1 motif, member 13” (ADAMTS13) plantation, drugs, autoimmune disease).
activity of 38%. These findings were consistent with HUS TTP is a primary TMA syndrome caused by a severe
secondary to S. pneumoniae. The patient received 4 doses reduction in the function of the von Willebrand factor–cleav-
of eculizumab with a good response; she completed antibi- ing protease ADAMTS13, which promotes the formation of
otic treatment, did not develop significant sequelae, and platelet microthrombi. TTP is classically described by the fol-
was later discharged. lowing pentad: MAHA, thrombocytopenia, fever, neurologic
symptoms, and AKI. Among the primary TMA syndromes,
INTRODUCTION TTP is remarkable for causing minimal kidney function
abnormalities.
Thrombotic microangiopathies (TMAs) are a group of disor-
DIC is an acquired systemic syndrome of the coagulation
ders characterized by injury and occlusion of microvessels
system resulting in consumptive coagulopathy, leading to
that arise from an endothelial injury, resulting in tissue
hemorrhage and pathologic thrombosis.
ischemia and end-organ damage. The TMA umbrella
includes but is not limited to HUS, thrombotic thrombocyto-
penic purpura (TTP), and disseminated intravascular coagul- EPIDEMIOLOGY
opathy (DIC). Given the overlap between presentations,
Most pediatric HUS cases worldwide are due to a STEC infec-
TMAs represent a diagnostic and therapeutic challenge for
tion (Figure 2). A total 90% of HUS cases are related to Shiga
clinicians.1 Due to the critical nature of acute TMAs, a signifi-
toxin–producing bacteria (E. coli, Shigella dysenteriae), 5% of
cant proportion of affected patients require admission to the
cases are attributed to S. pneumoniae or other secondary causes,
intensive care unit upon presentation, many of whom are not
and primary HUS accounts for 5% of cases. STEC-HUS is a
diagnosed at the time of admission. A thorough clinical and
disease of children mainly aged younger than 5 years; the inci-
laboratory evaluation is essential to arrive at an accurate diag-
dence peaks during summer and fall and varies depending on
nosis, which is key for appropriate management. HUS is a
geographic location.3 In North America and Europe, the
TMA that mainly affects the kidneys and is the most
annual incidence is 1.9 to 2.9 cases per 100 000 children aged
common cause of TMA in young children.2 HUS is classi-
3 to 5 years. However, the incidence of STEC-HUS in Latin
cally defined by the triad of microangiopathic hemolytic
America is 10 times higher.4 Of the patients with sporadic
anemia (MAHA), thrombocytopenia, and AKI. HUS can
STEC gastroenteritis, 5% to 10% develop HUS; however, that
be primary or secondary, both of which vary widely in
frequency can reach up to 20% during outbreaks.
severity and treatment. This article outlines the current
Primary HUS is a rare disorder; the annual incidence is
nomenclature for HUS as well as the initial diagnostic evalu-
estimated to be 0.23 to 0.42 cases per million.5
ation and management of HUS, particularly of primary
HUS, STEC-HUS, and S. pneumoniae HUS.
PATHOGENESIS
DEFINITIONS AND CLASSIFICATION The hallmark of HUS is a procoagulant and proinflammatory
Historically, HUS was classified as “diarrhea positive” (typi- state of activated endothelial cells and an overactivation of the
cal) and “diarrhea negative” (atypical). STEC-HUS was complement cascade.

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 FIGURE 1. Classification of HUS. C3, component 3; CFB, complement factor B; CFH, complement factor H; CFI, complement factor I;
DGKϵ, diacylglycerol kinase ϵ; MCP, membrane cofactor protein; THBD, thrombomodulin.

cycle.7 Hemolysis is due to intravascular red blood cell frag-

mentation. Complement activation can be initially triggered
by any stress on the body, such as an infection, surgery, or
inflammation.

Primary HUS
Primary HUS is a disorder of complement regulation due to
an underlying genetic predisposition. In healthy conditions,
the complement alternative pathway is constantly “on” but
tightly controlled. However, in primary HUS, the comple-
ment alternative pathway is inappropriately activated
through gain-of-function mutations (CFB or C3) or is unin-
FIGURE 2. HUS epidemiology. HUS, hemolytic uremic syndrome; hibited via loss-of-function mutations (CFH, CFI, MCP,
STEC, Shiga toxin–producing Escherichia coli THBD) of complement regulators or via autoantibodies to
CFH.1 The initial activation of complement is usually trig-
Complement is part of the innate immune response, gered by stress to the body. Overactivation of complement
assisting host cells in eliminating pathogens through 3 can be sustained or relapsing, leading to poor outcomes.
distinct pathways: classical, lectin, and alternative. These There are other rare genetic conditions that lead to
pathways converge to produce C3 convertase, a complex that permanent endothelial cell activation, such as coagulation
initiates the formation of the C5-9 membrane attack complex disorders, DKGϵ mutations, metabolism defects, and cobala-
(MAC) to destroy target cells by adhesion and lysis.6 min C deficiency.7
Activation of the MAC causes endothelial cell swelling and
microvascular thrombosis, particularly in the kidneys and, Secondary HUS
to a lesser extent, other organs. The endothelial damage Secondary HUS is caused by an internal or external event,
results in hemolysis, which can lead to further complement such as infections (STEC, S. dysenteriae, S. pneumoniae, influ-
activation, endothelial injury, platelet aggregation, and enza virus infections), cancer, transplantation, autoimmun-
microthrombi, which in turn causes further hemolysis that ity, or drugs. In these scenarios, once the trigger is removed
can lead to further complement activation, initiating a vicious or controlled, the HUS usually abates.

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 STEC-HUS is the most common cause of secondary HUS (acute respiratory distress syndrome, respiratory failure,
and the overall most common cause of HUS in the pediatric pleural effusion), cardiac (eg, arrhythmias, ischemia, cardio-
population.5 Shiga toxin–producing bacteria, particularly the myopathy, and pericardial effusion), and endocrine (insulin-
high-risk Shiga toxin 2 serotype bacteria, can precipitate this dependent hyperglycemia).
HUS.8 The most common E. coli serotype is E. coli O157:H7. A prodromal illness with emesis, diarrhea, and abdominal
Other non-O157 STEC strains and other Shiga toxin–produc- pain typically precedes the development of secondary HUS
ing bacteria, such as S. dysenteriae, have also been identified.8 precipitated by STEC. The diarrhea starts as nonbloody
The most common reservoir of E. coli O157:H7 is healthy cat- and progresses to bloody diarrhea in the first 3 days.8 The
tle, which transmit E. coli O157:H7 through their feces. Thus, microangiopathic changes occur by day 8 or 9 and anuria
infection in humans occurs after consumption of contami- before day 10.8 HUS almost always manifests 5 to 14 days
nated food or water (undercooked ground beef, unpasteur- after the onset of the prodrome. In S. dysenteriae secondary
ized dairy products, fresh produce), person-to-person HUS, the manifestations are usually more severe. S. pneumo-
contact, or contact with carrier animals. Shiga toxin is trans- niae–induced HUS occurs in individuals with severe
ferred into the bloodstream from the gastrointestinal tract by S. pneumoniae sepsis, usually presenting with complicated
attaching to the cell membrane receptor Gb3. Shiga toxin is pneumonia and, in some cases, with meningitis.
translocated into any cell that expresses the Gb3 receptor, par- In the setting of primary HUS, the onset of the disease
ticularly endothelial cells.8 Invasion of the toxin into endo- may follow a trigger event such as autoimmune conditions,
thelial cells precipitates cytotoxic damage. Microvascular transplantation, pregnancy, infections, drugs, or metabolic
injury initiates thrombotic responses such as platelet adhe- disorders. Primary HUS presentation is usually more severe
sion and microthrombi generation.8 Damage to endothelial and usually relapses without directed treatment.
cells in the kidney and large bowel can explain most of the The hallmark of HUS disease is the classic triad of micro-
signs and symptoms of HUS. However, other organs, includ- angiopathic hemolytic anemia, thrombocytopenia, and AKI.
ing the pancreas and central nervous system, can also be Rapidly progressive thrombocytopenia is the cardinal and
involved, which can have a direct correlation with the overall universal hematologic abnormality in patients with HUS.
extent of the disease. However, a transient decrease in platelet count may be
In the acute phase of secondary HUS, a decrease in C3 observed in patients with an STEC infection who do not
and C4 as well as an increase in complement degradation progress to HUS.8
products may be observed. However, no correlation with dis- Thrombocytopenia is defined by a platelet count below
ease severity and degree of changes in levels of C3, C4, and 150 000/μL or >25% decline from baseline. The severity
complement degradation products has been found. ranges from mild to severe. Despite the severity, there are
Another cause of secondary HUS in the pediatric popula- usually no clinical signs of thrombocytopenia (no petechiae,
tion is that induced by S. pneumoniae. The exact pathophysiol- purpura, or active bleeding).
ogy has not been determined. The neuraminidase produced Microangiopathic hemolytic anemia is caused by nonim-
by S. pneumoniae cleaves N-acetyl neuraminic acid (sialic acid), mune red blood cell fragmentation secondary to platelet
exposing the Thomsen-Friedenreich (TF) antigen on platelets, microthrombi and is characterized by anemia and markers
erythrocytes, and glomerular endothelial cells. Preformed of hemolysis as follows:
immunoglobulin M antibodies react to the expressed TF anti-
gen, precipitating the complement cascade leading to HUS. • Hemoglobin levels are usually less than 8 g/dL
• Negative direct antiglobulin test (DAT, formerly referred to
as the Coombs test; DAT can be positive in the case of
CLINICAL ASPECTS pneumococcal HUS)
Clinical Manifestations • Peripheral blood smear with schistocytes (including hel-
The clinical presentation of HUS is nonspecific. Signs and met cells and micro spherocytes; Figure 3)
symptoms include weakness, fatigue, pallor, shortness of • Increased serum indirect bilirubin concentration
breath, decreased urine output, and severe hypertension. • Reduced serum haptoglobin concentration
Systemic signs of HUS vary significantly between patients, • Hemoglobinuria
depending on the organs affected by the HUS process. • Elevated serum LDH
Extrarenal manifestations include but are not limited to neu-
rologic (eg, seizures, stroke, coma), gastrointestinal (eg, hem- Another constant finding is severe hypertension secon-
orrhage, perforation, pancreatitis, cholestasis), pulmonary dary to endothelial swelling. The severity of kidney disease

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 always fatal if appropriate treatment with plasmapheresis
is not promptly initiated.
Once the diagnosis of HUS is established, the goal is
to identify the underlying etiology. If the patient presents
with a history of recent diarrhea, regardless of the pres-
ence or absence of blood in the stool, a detailed investi-
gation for Shiga toxin–producing bacterial infection
should be conducted with stool studies. A pneumococcal
infection should always be considered in the pediatric
population based on clinical presentation; thus, the
workup should include nucleic acid tests or cultures
for S. pneumoniae.
When primary HUS is suspected, complement activa-
tion tests should be obtained (Figure 5). Low serum C3
and normal C4 levels indicate alternative complement
pathway activation. Nonetheless, this is a nonspecific
and nonsensitive marker, as not all patients present with
FIGURE 3. Peripheral blood smear showing an example of a hypocomplementemia. Patients with an overactivation of
schistocyte the alternative complement cascade present with an
elevation of the MAC, measured by soluble C5b-9. The
ranges from proteinuria and microscopic hematuria to latter is presumed to be an objective form of measuring
severe AKI, gross hematuria, and oliguria requiring kidney complement activation.4,9
replacement therapy. Primary HUS should be suspected when secondary HUS,
In 50% to 60% of children with secondary STEC-related TTP, or DIC are ruled out (Figure 6). At present, there is no
HUS, oliguria is reported.8 Hemoglobinuria is a constant specific diagnostic test for primary HUS. The number of new,
finding in patients with secondary STEC-related HUS, as it discovered genetic abnormalities associated with primary
reflects intravascular hemolysis that exceeds the resorptive HUS continues to increase over time, but many forms remain
capacity of the kidneys.
unknown or poorly understood. At present, 45% of the
patients with primary HUS have an identifiable genetic
APPROACH TO DIAGNOSIS variant.5 Genetic workup for suspected primary HUS should
The diagnostic approach to a patient with suspected HUS include screening for complement regulator mutations
should be implemented promptly to decrease morbidity and other rare causes, such as DGKϵ genetic variants
and mortality. A useful diagnostic approach for patients sus- (at least for children up to age 6 years), testing for CFH auto-
pected of HUS is outlined in Figure 4. This approach relies antibodies, and searching for inborn errors of metabolism
on stepwise laboratory analysis. such as cobalamin C deficiency (especially in infants younger
Recognition of TMA is the first step in the diagnostic path- than age 1 year).7 Confirmation of a genetic abnormality is
way. To do so, laboratory evaluation should include a com- not required for diagnosis or management decisions of
plete blood count, peripheral blood smear, reticulocyte primary HUS.
count, LDH level, indirect bilirubin levels, haptoglobin level, In all cases of HUS, nephrology and hematology services
a direct antiglobulin test, and a urinalysis. Once the presence should be consulted for appropriate management.
of TMA is identified, evaluation of end-organ damage should
commence. For the latter, it is necessary to assess renal, car-
diac, pulmonary, neurologic, and gastrointestinal function. DIFFERENTIAL DIAGNOSIS
Laboratory evaluation should include a complete metabolic The diagnosis of HUS can be challenging because the syn-
panel and troponin, lactate, lipase, and liver enzyme levels. dromes TTP and DIC can mimic its presentation. The pres-
Coagulation studies, including PT, aPTT, D-dimer, and ence of microangiopathic hemolytic anemia and thrombo-
fibrinogen, should be obtained to rule out DIC. The next step cytopenia should prompt the search for these life-threatening
should be to rule out TTP by assessing ADAMTS13 activity, conditions. TTP, DIC, and HUS share clinical manifesta-
which would be decreased in such disease (<10%). This step tions and laboratory markers (Figure 6). Early recognition
is crucial, as TTP is a medical emergency that is almost can facilitate the timely implementation of specific

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 FIGURE 4. Diagnostic and therapeutic algorithm in primary TMA. ADAMTS13, a disintegrin and metalloproteinase with thrombospondin type
1 motif, member 13; cblc, cobalamin C; DAT, direct antiglobulin test; DGKϵ, diacylglycerol kinase ϵ; HUS, hemolytic uremic syndrome; LDH,
lactate dehydrogenase; TTP, thrombotic thrombocytopenic purpura.

FIGURE 5. Genetic and immunological studies of the alternative complement pathway. SC5b-9, soluble terminal complement complex
enzyme.

treatments. TTP usually presents later in life but can happen excessive systemic activation of coagulation, resulting in
in childhood and usually presents with more severe hemorrhage and thrombosis. Thus, coagulation studies
thrombocytopenia, neurologic manifestations, fever, and are usually abnormal, with high PT, high aPTT, low fibrino-
less kidney involvement; an ADAMTS13 activity of less than gen, high D-dimer, and with hemolysis being less
10% confirms its diagnosis. DIC is characterized by an pronounced.

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 FIGURE 6. Differential diagnosis: HUS, TTP, and DIC. ADAMTS13, a disintegrin and metalloproteinase with thrombospondin type 1 motif,
member 13; DIC, disseminated intravascular coagulopathy; HUS, hemolytic uremic syndrome; INR, international normalized ratio; PT,
prothrombin time; PTT, partial thromboplastin time; TTP, thrombotic thrombocytopenic purpura.

MANAGEMENT the conversion of C5 to C5a and C5b, thereby preventing

Supportive therapy is the backbone of HUS management, the generation of the MAC.7 Of note, the blockage
which has largely contributed to the reduction in mortality of the complement alternative pathway cascade puts children
once microangiopathy develops. The administration of intra- at risk for Neisseria meningitidis infection.
venous isotonic fluids prior to the onset of HUS in patients Even though in secondary HUS there is an overactivation
with suspected and/or confirmed STEC infection is a simple of the complement cascade, it is usually self-limited when the
and potentially beneficial intervention to reduce morbidity trigger abates. Thus, the use of terminal blocking agents in
among affected children.10 The stool of all children with a secondary HUS is controversial and reserved for patients
clinical picture indicative of possible STEC infection should who are severely ill and for whom an underlying primary
be evaluated for pathogen detection, explicitly looking for HUS cannot be fully excluded.
the high-risk serotype Shiga toxin 2.8 In children with hemo-
dynamic instability and multiorgan dysfunction, renal PROGNOSIS
replacement therapy should be considered. The replacement With prompt recognition and appropriate supportive care, the
of packed red blood cells is generally required. However, mortality rate for STEC-HUS is less than 5% in children.11
platelet transfusions should be limited to patients with sig- Such deaths are usually attributed to neurologic complications
nificant bleeding because HUS complications are related (ie, seizures, coma, or stroke). Up to 50% of patients may
to thrombotic injury.8 require kidney replacement therapy during the acute phase
In patients with STEC infection, the administration of of the disease. Within 1 to 2 weeks, the hematologic manifes-
antibiotics, narcotics, and antimotility agents has been tations usually resolve. Some children recover renal function
observed to prolong the course of bloody diarrhea and completely, 5% remain dependent on dialysis, and up to 50%
increase the risk for developing HUS and neurological com- are left with some degree of kidney damage. Hence, patients
plications; therefore, such interventions should be strongly with HUS secondary to STEC should undergo yearly follow-
discouraged, and instead allow the infection to follow its ups to monitor for signs of proteinuria, hypertension, and
self-limiting course. On the contrary, patients with a deterioration of renal function, with continued monitoring
pneumococcal infection should be treated with proper anti- throughout adulthood. There is evidence that children with
biotic therapy to manage the specific infection. HUS secondary to STEC who initially present with high
Until recently, primary HUS was treated with plasma hematocrit levels (>23%) and who do not receive intravenous
exchange therapy, which has variable response. Often, chil- fluids prior to the establishment of HUS have poorer out-
dren would live with relapses or very severe disease leading to comes, including oliguria, the need to use kidney replacement
end-stage renal failure or death. Nowadays, the current stan- therapy, and death.12
dard of treatment for primary HUS is initiating a terminal HUS that is related to pneumococcal infections is usually
complement blocking agent (anti-C5) such as eculizumab associated with an increase in morbidity, with more than
or ravulizumab, especially if kidney function is rapidly 80% requiring dialysis and a mortality rate of up to 20%.
deteriorating during workup. These agents are humanized Primary HUS tends to be insidiously progressive with inter-
monoclonal antibodies against complement C5 that block mittent relapses. Regardless of whether a genetic abnormality

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 is identified, patients with primary HUS have devastating (ie, schistocytes, helmet cells) is necessary when
outcomes if not initiated on an anticomplement agent.2 HUS is suspected.14 (Based on strong evidence.)
Although the use of anticomplement treatment in patients • Monitoring of hemoglobin, platelet count, electro-
with primary HUS improves kidney-related outcomes, unjus- lytes, and kidney function is recommended to
tified use of such therapy may be harmful. Thus, nephrology detect early manifestations of HUS in patients with
and hematology experts should always be consulted. STEC infection.14 (Based on strong evidence.)
• There is an association between dehydration and
CONCLUSION adverse outcomes in children with HUS. Thus,
Primary HUS describes an underlying dysregulation of the intravenous hydration is crucial during the diar-
alternative complement pathway with an underlying genetic rhea phase of STEC infection, as it reduces the risk
predisposition, whereas secondary HUS is caused by some of oliguric renal failure in those children who
internal or external insult (infection, malignancy, transplan- develop HUS.10,14 (Based on strong evidence.)
tation, drugs, autoimmune disease). In the pediatric popula-
• It is recommended to avoid the use of antibiotics
tion, 90% of HUS cases are related to an STEC infection.
in individuals infected with STEC, as there is a sig-
However, it is essential to know that severe S. pneumoniae
nificant positive association between antibiotic
infection can also cause HUS.
administration and the risk of developing HUS.14
Close monitoring of children with highly suspected or
(Based on strong evidence.)
diagnosed STEC infection is crucial. Avoiding potentially
harmful interventions and preventing volume depletion
might prevent complications.
IDEAS FOR QI PROJECTS
It is fundamental that pediatricians develop the ability to
recognize the different signs and symptoms of HUS as well • Decrease the use of antibiotics in patients with acute
as to initiate primary evaluation. Early recognition of the under- bloody diarrhea or highly suspected STEC infection.
lying etiology of HUS is important for prompt treatment. • Increase early aggressive intravenous hydration for
patients with highly suspected STEC infection.
• Implementation of a clinical pathway for the evaluation of
patients with highly suspected STEC infection and pos-
Summary sible HUS.
• Stool samples should be submitted for the detec-
tion of bacterial pathogens in children with hem-
atochezia or nonbloody diarrhea accompanied by
severe abdominal pain or tenesmus.13 (Based on Take the quiz! Scan this QR code to take the quiz,
access the references, and view and save images
strong evidence.)
and tables (available January 1, 2025).
• Examining the peripheral blood smear for the
presence of red blood cell fragmentation

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 PIR QUIZ

1. A previously healthy 5-year-old boy is brought to the emergency department

(ED) by his parents because of a 1-day history of pallor, fatigue, swelling
around the eyes, and decreased urine output. There is no associated fever,
vomiting, or diarrhea. Past medical history is significant for a febrile illness 10
days ago with several episodes of nonbilious emesis, nonbloody diarrhea, and
crampy abdominal pain after attending a state fair petting zoo 2 days prior.
The diarrhea became bloody on the second day of illness and resolved with
supportive care at home on day 3. The patient was seen in urgent care at
that time and presumed to have an acute gastroenteritis. Stool studies were
ordered for polymerase chain reactions and ova and parasites. The patient
could not provide a stool sample in urgent care and was sent home with his
parents to collect the stool sample with the next bowel movement, but the REQUIREMENTS: Learners can
parents did not collect, as his diarrhea resolved. On physical examination in take Pediatrics in Review quizzes
and claim credit online only at:
the ED today, he is afebrile with stable vital signs. Examination is remarkable
http://pedsinreview.org.
for periorbital edema and pale conjunctivae. He is admitted to the hospital
for further workup and management. In addition to evidence of To successfully complete 2025
thrombocytopenia and acute kidney injury, the presence of which of the Pediatrics in Review articles for
following additional laboratory findings is most likely to confirm the diagnosis AMA PRA Category 1 Credit™,
learners must demonstrate a
of secondary hemolytic uremic syndrome (HUS) in this patient?
minimum performance level of
A. Cobalamin C deficiency 60% or higher on this
assessment. If you score less than
B. Complement regulator mutations
60% on the assessment, you will
C. DGKϵ genetic variants be given additional opportunities
D. Low serum C3 and normal C4 levels to answer questions until an
E. Microangiopathic hemolytic anemia overall 60% or greater score is
achieved.
2. A 12-year-old girl is admitted to the hospital for management of secondary
HUS that occurred after eating a hamburger from a street vendor in her This journal-based CME activity is
neighborhood. This patient’s condition is most likely caused by Shiga toxin available through Dec. 31, 2027,
produced by which of the following pathogens? however, credit will be recorded
in the year in which the learner
A. Campylobacter jejuni completes the quiz.
B. E. coli O157:H7
C. Giardia lamblia
D. Helicobacter pylori
E. Salmonella typhi
3. While rounding on the patient in the above vignette, the attending physician
provides the team with an explanation of the pathophysiologic mechanism in 2025 Pediatrics in Review is
approved for a total of 30
which the Shiga toxin leads to the findings in secondary HUS. The Shiga toxin
Maintenance of Certification
causes secondary HUS through which of the following toxin-induced (MOC) Part 2 credits by the
pathophysiologic mechanisms? American Board of Pediatrics
(ABP) through the AAP MOC
A. Activation of autoantibodies
Portfolio Program. Pediatrics in
B. Cleavage of N-acetylneuraminic acid (sialic acid), exposing the Thomsen- Review subscribers can claim up
Friedenreich antigen on platelets, erythrocytes, and glomerular to 30 ABP MOC Part 2 points
endothelial cells upon passing 30 quizzes (and
C. Complement dysregulation with activation of complement alternative claiming full credit for each quiz)
per year. Subscribers can start
pathway
claiming MOC credits as early as
D. Invasion of endothelial cells leading to endothelial cytotoxic cell damage October 2025. To learn how to
with secondary platelet adhesion and microthrombi claim MOC points, go to: https://
E. Severe reduction in the function of the von Willebrand factor–cleaving publications.aap.org/journals/
protease ADAMTS13, which promotes the formation of platelet pages/moc-credit.
microthrombi

Vol. 46 No. 1 J A N U A R Y 2 0 2 5 11

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by Tomas Krepostman
 4. A 6-year-old boy is brought to the ED by his parents because of a 1-day
history of progressively worsening watery diarrhea and crampy abdominal
pain associated with fever and decreased oral intake. The last bowel
movement was bloody, which prompted the ED visit. There is a history of sick
contacts with multiple classmates with similar symptoms. On physical
examination, his temperature is 38.8 °C. He is tachycardic with dry mucous
membranes. His abdomen is diffusely tender with no rebound and
hyperactive bowel sounds. The remainder of the examination is
unremarkable. Stool studies were positive for E. coli O157:H7. Which of the
following is the most appropriate next step in management?
A. Intravenous isotonic fluids
B. Intravenous narcotics
C. Oral antibiotics
D. Oral antimotility agents
E. Oral hydration with water
5. A child is diagnosed with primary HUS. Among the following management
strategies, administration of which one of the following is most likely to
contribute to improved outcome in this patient?
A. Antibiotics
B. Fresh frozen plasma
C. Plasma exchange therapy
D. Red blood cell transfusion
E. Terminal complement (C5) blocking agent

12 Pediatrics in Review

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by Tomas Krepostman