Hemolytic Uremic Syndrome - A Different Story

K. Obata
Department of Pediatrics
Division of Critical Care Medicine
Washington University School of Medicine
St. Louis Children's Hospital
St. Louis, MO

REPORT OF CASE:

The patient is a 2 year and 9 month old African-American male who was previously healthy except for mild asthma. He had been doing well until 6 days prior to admission when he developed a fever of 102°F and mild respiratory distress. He was seen in the emergency room 5 days prior to admission and was diagnosed with an exacerbation of his asthma. He was treated with nebulized albuterol. No antibiotics were administered, and he was discharged home.

His respiratory status worsened with increased work of breathing; the intermittent fever persisted. Although his appetite was decreased, he maintained adequate fluid intake and urine output. He was also treated at home for constipation with 3 Fleets enemas.

He returned to the emergency room on the day of admission with the complaint of worsening respiratory distress and fever.

Physical examination revealed an irritable child with temperature of 38°C, pulse of 180/min, respiratory rate of 40 to 70/min, blood pressure of 118/58 mmHg, SpO2 of 82% on room air. His body weight was 11.5 kg.

He had nasal flaring, grunting, expiratory wheezing, and markedly decreased air entry on the left side of the chest. He was well perfused; his heart sounds were normal and his abdomen was soft. No skin lesions were noted. Neurological examination was normal except for his irritability.

The chest radiograph showed opacification of the left hemithorax. A chest tube was placed and a significant amount of thick serosanguinous fluid was drained. He was diagnosed with pneumonia with an exudative pleural effusion.

He was transferred to the PICU for close observation due to his tenuous respiratory status. Treatment was continued with oxygen by nasal cannula, antibiotics (cefotaxime and oxacillin), and fluid management.

The initial labs were as follows.
WBC 3,600/mm3 (18B,62S,17L,3M) Hb 9.3g/dL Ht 27.6% Plt 111,000/mm3
Na 129 mEq/L K 3.2 mEq/L Cl 94 mEq/L CO2 23 mEq/L BUN 10 mg/dL Cr 0.3 mg/dL glucose 99mg/dL
VBG: pH 7.38 pCO2 46 mmHg pO2 62 mmHg HCO3 25 mEq/L
Pleural fluid: bloody with a total cell count 50,000/mm3 WBC 3,200/mm3 (64S,36L) glucose 26mg/dL total protein 4.9g/dL
Urinalysis: specific gravity 1.020 pH 6.0 hemoglobin 2(+) protein 3(+)
glucose (-) ketone 1(+) bilirubin (-) reducing substance (-) WBC 2-4/HPF
RBC 14-16/HPF epithelial cells 3-5/HPF
Blood culture and pleural fluid culture: (+)Streptococcus pneumoniae (sensitive to penicillin)
Urine culture and tracheal aspiration culture (-)

18 hours after admission to PICU, he developed striking jaundice, poor perfusion, and diminished urine output. The urine was dark red.

Laboratory studies at this time revealed:
WBC 5400 Hb 4.0 Hct 11.7 Plt 13000 reticulocytes 0.1 %
Na 138, K 3.9 Cl 109 CO2 24 BUN 46 Cr 0.8 glucose 87
ABG: pH 7.29 pCO2 39 pO2 114 HCO3 19
Total bilirubin 18.2 mg/dL conjugated bilirubin 17.5mg/dL
LDH 16,700 U/L AST 266 U/L ALT 30 U/L ALP 170 U/L GTP 24 U/L Alb 2.3g/dL total protein 5.0g/dL
PT 16.1sec PTT 59.8sec fibrinogen 558mg/dL FDP > 40 microgram/mL
Urinalysis: pH 6.5 hemoglobin 3(+) protein 3(+) glucose (-) bilirubin 3(+) ketone trace WBC 3-5 RBC numerous epithelial cells 10-12 granular cast 0-3

Invasive monitoring was begun with central and arterial catheters, a bladder catheter was placed, vancomycin was started, oxacillin was discontinued, and dopamine was started at a rate of 3 micrograms/kg/min. Packed red blood cell, fresh frozen plasma, and platelet transfusions were given.

He subsequently developed increasing respiratory distress with retractions, as well as mild bleeding from the oral cavity. An arterial blood gas revealed a pH of 7.22, pCO2 50, pO2 96, HCO3 21. His trachea was intubated and mechanical ventilation was begun.

Thirty-six hours after admission, his urine output decreased further and his renal function progressively deteriorated with the creatinine rising from 1.2 to 2.1 and BUN from 61 to 92. The blood pressure was markedly elevated and the CVP increased from 7 mmHg to 19 mmHg. He was treated with diuretics and fluid restriction with some response; the CVP declined to 13. Dopamine was discontinued and dobutamine initiated.

In further assessing the etiology of this massive hemolytic anemia, a peripheral blood smear revealed no Heinz bodies and a mixed picture of spherocytes and microangiopathic hemolysis. The direct Coombs test was positive.

He developed progressive azotemia, thrombocytopenia, and metabolic acidosis. A pericardial friction rub was audible, and an echocardiogram demonstrated a small pericardial effusion. A renal ultrasound showed normal sized kidneys with no evidence of renal vein thrombosis. On day 3 of admission, a peritoneal catheter was placed and peritoneal dialysis was started.

During the next 3 days he required 2 more transfusions of red blood cells and platelets; the reticulocyte count remained low. On day 5 methylprednisolone 2mg/kg IV q day was started for 4 days in an effort to reduce immune-mediated hemolysis. On day 6 hemolysis became less severe with an increasing reticulocyte count and stable hemoglobin level without transfusions. The ventilatory support was reduced.

On hospital day 9, he was extubated and on day 10 urine output improved (1.0 ml/kg/hr) after 3 days of anuria. On day 12, patient was transferred from PICU. On day 16 peritoneal dialysis was discontinued. By day 22, his renal function was normal.

He subsequently developed Klebsiella peritonitis, candida central line infection and recurrent empyema which were treated with intraperitoneal gentamicin, systemic Amphotericin B, and operative decortication. On discharge on day 32, his BUN, Cr, WBC count, platelet count and blood pressure were all normal. The Hb was marginally abnormal at 9.7.

After discharge, he later developed a markedly dilated gallbladder and a cystic duct containing sludge, possibly related to microangiopathy involving the biliary tree.

DISCUSSION

This is a rare but an illustrative case of hemolytic-uremic syndrome (HUS) which was associated with pneumococcal pneumonia.

HUS is a syndrome with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. This syndrome was first described in 1955 by Gasser and colleagues (1). It is usually preceded by a prodrome of gastroenteritis with hemorrhagic colitis. In early 1980's, the association between enterohemorrhagic Escherichia coli serotype O157:H7 and HUS was reported (2,3). Enterohemorrhagic E coli infections are now recognized to be responsible for majority of HUS cases in the United States.

Although approximately 90% of childhood cases of HUS follow a diarrheal prodrome (classic or typical HUS), a variety of conditions are known to trigger this syndrome without gastrointestinal infections (atypical HUS). These include nonenteric infections, drugs, malignancies, systemic disorders, primary glomerulopathies. Some familial cases have also been reported.

Streptococcus pneumoniae infections, particularly pneumonia (rarely meningitis) are known to cause HUS and are the most commonly reported examples of nondiarrheal HUS in children. Sporadic case reports have been accumulating (4,5,6,7) and the largest case series (7 cases) of HUS associated with invasive S. pneumoniae infection to date was recently reported by Cabrera and colleagues (8).

Although the pathogenesis of classic HUS is not completely understood, it is proposed that Shiga-like toxin and lipopolysaccharide produced by enterohemorrhagic Escherichia coli and other intestinal organisms gain entrance to the circulation and cause endothelial cell injury both directly and indirectly via various inflammatory mediators (9). The pathogenesis of HUS associated pneumococcal infection appears to involve a unique antigen-antibody interaction.

Following a few reports in the European literature, Klein and colleagues (10) found Thomsen-Friedenreich antigen (T-antigen) on erythrocytes and in the glomeruli of two 1-year-old children who died from HUS secondary to pneumococcal pneumonia with sepsis in 1977. This T-antigen exists on the surfaces of red blood cells, platelets and endothelial cells. However, it is normally covered by N-acetyl neuraminic acid moieties on the membrane surfaces. Circulating neuraminidase released from certain organism such as Streptococcus pneumoniae removes the N-acetylneuraminic acid from the cell membrane. The T-antigen then reacts with naturally occurring IgM anti-T antibody present in most normal sera. This interaction causes damage leading to the clinical manifestations of HUS. It was speculated that this is the pathogenesis of HUS due to Streptococcus pneumoniae infections. They also confirmed weak IgM deposits in the glomeruli indicative of the antigen-antibody reaction (10).

Novak and colleagues (5) described three infants with HUS associated with pneumococcal pneumonia and supported this link between T-antigen and HUS. In all three patients, they found evidence of T-antigen exposure and exsistence of serum neuraminidase activity from organism-free filtrates. These two findings were not detected in 125 preoperative control patients and organism-free filtrates from patients with pneumococcal infection without HUS, respectively.

Based on this finding, it was suggested that treatment with plasma products containing anti-T antibody may be potentially hazardous and worsen hemolysis. Therefore anti-T free blood products (e.g., washed red blood cells) was recommended (6). With our case, we could not avoid transfusion of blood products even after diagnosis of HUS because of the clinically severe hemolytic anemia and thrombocytopenia.

The positive direct Coombs test in our case made the initial diagnosis of HUS difficult because a positive Coombs test usually suggests immune hemolytic anemia whereas microangiopathic hemolytic anemia is usually the case with typical HUS. This postive Coombs test is considered to be a result of the T-antigen antibody reaction (7). It can be an important clue to suggest the diagnosis of HUS secondary to neuraminidase producing organisms. The peripheral blood smear showed a mixed picture of microangiopathic and immune hemolysis.

The urinalysis on admission in our patient showed proteinuria and microscopic hematuria suggesting that there was already some evidence of renal injury despite adequate urine output and the absence of azotemia. There may also have been hemoglobinuria distinct from the hematuria suggesting intravascular hemolysis. His maximum BUN/Cr was 113/2.8 on day 3 before the dialysis was started and his renal function was normal on day 22. The duration of anuria was 3 days, oliguria 7 days, and peritoneal dialysis 13 days. He had no neurologic manifestations.

Siegler and colleagues found that duration of anuria was the best predictor of renal outcome with HUS. No patients who had anuria lasting longer than 8 days or oliguria exceeding 15 days escaped chronic renal disease (11). However no data exist regarding long-term renal function in HUS associated with pneumococcal infection. Periodic evaluation for an extended period will be essential for these patients.

REFERENCES

1. Gasser, et al. Haemolytisch-Uraemiche Syndrome. Schweiz Med Wochenschr. 1955; 85: 905
2. Riley LW, et al. Hemorrhagic colitis associated with a rare Escherichia coli serotype. N Engl J Med. 1983; 308(12): 681-685.
3. Karmali MA, et al. Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing Escherichia coli in stools. Lancet. 1983; 1(8325): 619-62
4. Moorthy B, et al. Hemolytic-uremic syndrome associated with pneumococcal sepsis. J Pediatr. 1979; 95(4): 558-559.
5. Novak RW, et al. Hemolytic-uremic syndrome and T-cryptantigen exposure by neuraminidase-producing pneumococci: an emerging problem? Pediatr Pathol. 1983; 1(4): 409-413
6. McGraw ME, et al. Haemolytic uraemic syndrome and the Thomsen Friedenreich antigen. Pediatr Nephrol. 1989; 3(2): 135-139.
7. Erickson LC, et al. Streptococcus pneumoniae-induced hemolytic uremic syndrome: a case for early diagnosis. Pediatr Nephrol. 1994; 8(2): 211-213.
8. Cabrera GR, et al. Hemolytic uremic syndrome associated with invasive Streptococcus pneumoniae infection. Pediatrics. 1998; 101(4 Pt 1): 699-703
9. Siegler RL. The hemolytic uremic syndrome. Pediatr Clin North Am. 1995; 42(6): 1505-1529
10. Klein PJ, et al. Thomsen-Friedenreich antigen in haemolytic-uraemic syndrome. Lancet. 1977; 2(8046): 1024-1025
11. Siegler RL, et al. Long-term outcome and prognostic indicators in the hemolytic-uremic syndrome. J Pediatr. 1991; 118(2): 195-200.

Acknowledgement: Appreciation to Dr. Anne Beck for reviewing this report.

Permission to describe this case was obtained from the patient's guardian

Back to Rare Case Index Page