Key Clinical Message
Causative factors of HUS due to infection are not limited to classic
EHEC and Shigella infection. Understanding the effects of EPEC related
HUS and its complications is imperative for early diagnosis and
treatment to mitigate long term sequelae.
Background :
Hemolytic uremic syndrome (HUS) is a potentially life-threatening
hematologic disorder that presents with the triad of microangiopathic
anemia (MAHA), thrombocytopenia and acute renal failure secondary to
vascular damage. The typical form of HUS (tHUS) is caused by an E.
coli or Shigella infection, most commonly enterohemorrhagicE. coli (EHEC) strain O157:H71. Atypical HUS
(aHUS) is caused by a genetic mutation causing abnormal complement
activation. Enteropathogenic E. coli (EPEC) is a well-known cause
of diarrhea in pediatric patients who live in developing countries, but
is a rare cause of adult diarrhea, and has not been documented as a
cause of HUS2. Here we report a unique case of HUS
secondary to EPEC infection, with a discussion on the diagnosis of HUS
and how it is distinguished from other thrombotic microangiopathies
(TMA).
Case Report :
A 64-year-old female with a history of early stage, hormone positive
breast cancer (treated with partial mastectomy in January 2019 and
hormone therapy) presented with weakness, fatigue, nausea, vomiting, and
watery, non-bloody diarrhea that started within 48 hours after eating
restaurant food. In the emergency department, max temperature was 37.4 ℃
(99.3 °F), heart rate was 156, and blood pressure was 95/63. She was
alert and oriented to person, place, time and situation. Her white blood
cell count (WBC) was 21,430/uL, hemoglobin (HGB) 14.8 g/dL, platelet
count (PLT) 227,000/uL, potassium 3.5 mEq/L, lactate 8.68 mg/dL,
creatinine 2.2 mg/dL, BUN 37 mg/dL, and creatine kinase (CK) 10,846 U/L.
She was diagnosed with hypovolemic shock and acute kidney injury
secondary to rhabdomyolysis. She was given aggressive IV hydration with
empiric antibiotics and was sent to the ICU for higher level of care.
Over the next 5 days, she developed severe thrombocytopenia and anemia,
reaching a nadir PLT count of 50 and HGB of 5.0. She was anuric and
transitioned from continuous renal replacement therapy to conventional
hemodialysis. Complement levels were low during this acute stress state.
Blood smear showed the presence of many schistocytes and reticulocytosis
(Figure 1), and labs (Table 1) confirmed hemolysis. Cold agglutinin
test, paroxysmal nocturnal hemoglobinuria markers, antinuclear antibody
and direct antibody testing were negative. Fecal pathogen polymerase
chain reaction (PCR) testing was positive for EPEC. ADAMTS13 activity
level was decreased at 32% (normal is greater than 67%), but did not
meet thrombotic thrombocytopenic purpura’s (TTP) diagnostic criteria
(below 5-10%); hence, plasmapheresis therapy was not performed.
Atypical HUS genetic panel was negative, and C1 esterase inhibitor level
was within normal limits.
Clinical improvement began after steroid therapy. She was started on IV
methylprednisolone 1 mg/kg/day for 12 days. She then transitioned to
prednisone 60 mg daily, and tapered the dose down by 20 mg each week.
After she completed week 3 of prednisone therapy (20 mg daily), the dose
was reduced to 10 mg daily for the final week. Mentation improved, and
repeat blood smear showed significantly fewer schistocytes compared to
before. Her CBC and CMP values recovered, as did hemolysis labs (Table
1). She was on hemodialysis for a total of 5 weeks. She can now live
independently, but residual symptoms include moderate fatigue, weakness,
and decreased cognition.
Discussion :
Documented cases of typical HUS in adult patients are very rare, and
usually are caused by O157:H7 strains of E. coli that can be
cultured and/or detected by stool studies that detect the organism’s
Shiga-like toxins stx1/stx23,4. This case is a rare
example of HUS in an adult patient whose fecal pathogen PCR was positive
for EPEC rather than EHEC.
EPEC produces the watery diarrhea seen in this patient case, whereas
EHEC causes bloody diarrhea. EPEC produces an attaching and effacing
lesion (A/E) upon the epithelial surface of the small and/or large
bowel. It then utilizes a type III secretion system to inject virulence
factors into host cells, and a type IV bundle forming pilus to establish
microcolonies. It is hypothesized that EPEC causes watery diarrhea by
disrupting the absorptive surfaces of the intestinal
microvilli5. EHEC also forms A/E lesions on the
intestinal epithelium, as it shares the same chromosomal pathogenicity
island as EPEC. However, what distinguishes EHEC is the production of
Shiga-like toxin, which binds to endothelial cells that express Gb3 and
enables diffuse spread of the toxin to various cells (including renal
glomerular endothelium) that express Gb3. Moreover, EHEC causes bloody
diarrhea but EPEC does not because the A subunit of EHEC’s Shiga-like
toxin prevents protein synthesis and triggers apoptosis of the host
cells6.
Typical HUS, atypical HUS and TTP are all causes of MAHA, but each have
distinct mechanisms. tHUS is caused by EHEC’s verotoxins orShigella ’s enterotoxins, which cause vascular damage
(specifically to the glomerular endothelium) and thereby increase
platelet adhesion and promote microthrombi formation7.
In contrast, aHUS is unrelated to E. coli or Shigellainfection and is instead caused by abnormal regulatory genes of the
complement pathway. TTP is caused by antibodies disrupting the ADAMTS13
enzyme, resulting in the accumulation of von Willebrand factor multimers
that cause MAHA. Another type of HUS that does not fit into the typical
or atypical categories is secondary HUS, which may be caused by
streptococcal infection or other acquired sources of complement
dysregulation such as pregnancy, chemotherapy, malignancy, glomerular
disorders, or autoimmune diseases. If the patient has no genetic
abnormalities in the complement pathway, no identifiable causes of
secondary HUS, and normal ADAMTS13 activity, then the TMA is idiopathic
HUS8.
Where on the complex spectrum of HUS does this patient’s case belong?
She did not have an EHEC or Shigella infection and no Shiga or
Shiga-like toxins were identified, so her TMA cannot be diagnosed as
tHUS. On the other hand, with no genetic abnormality in complement
regulation, the patient does not meet the criteria for aHUS either.
Since the suspected cause of her TMA is EPEC, her case is best described
as HUS secondary to EPEC infection. Although the possible mechanisms of
EPEC-related HUS have not yet been elucidated, tHUS, aHUS, and TTP are
all ultimately consequences of complement system hyperactivation; thus,
it is feasible that EPEC’s effect on the host systemic inflammatory and
complement pathways could also incite HUS despite lacking EHEC’s
Shiga-like toxins9.