Haemolytic–uraemic syndrome following human parvovirus infection in a previously fit adult

Edward W. Seward, Rana Rustom, Frederick J. Nye1 and J. Michael Bone

Regional Renal Unit, Royal Liverpool University Hospital, NHS Trust and 1 Regional Centre for Infectious Disease, Fazakerley Hospital, Aintree NHS Trust, Liverpool, UK

Correspondence and offprint requests to: Dr Rana Rustom, Senior Registrar Nephrology, Royal Liverpool University Hospital, Link 6c, Prescot St., Liverpool L7 8XP, UK.

Keywords: haemolytic–uraemic syndrome; human parvovirus



   Introduction
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 Introduction
 Case
 Discussion
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Human parvovirus infection recently has been increasingly described in association with various glomerulonephritides [13]. To the best of our knowledge, there have been no previous reports of haemolytic–uraemic syndrome (HUS) following parvovirus infection in a previously fit man.



   Case
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 Case
 Discussion
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A previously healthy 34-year-old male developed a rash over 2 weeks, followed by a flu-like illness over 3 days, and severe abdominal pain. He had a symmetrical polyarthralgia and severe weakness. He was drowsy and pyrexial (38.5°C), with a blotchy erythematous maculopapular rash of his face, ears, neck and upper trunk. His blood pressure was 150/90 mmHg, and he had marked submandibular lymphadenopathy, hepatosplenomegaly (confirmed by abdominal ultrasound) and painful testicular swelling. There were no focal neurological signs. He had thrombocytopenia, mild lymphopenia, monocytosis, renal impairment and hepatic dysfunction (haemoglobin 12.1 g/dl, platelets 54x109/l, white cell count 9.1x109/l, lymphocytes 0.9x109/l, monocyte count 1.0x109/l, serum urea 9.2 mmol/l, creatinine 132 µmol/l, albumin 25 g/l, bilirubin 17 µmol/l, {gamma}GT 90 U/l, ALT 68 U/l and ALP 139 U/l. The serum amylase was normal. A liver biopsy (via laparotomy) the following day revealed only an acutely congested liver. A bone marrow biopsy was normal.

One week later, he was intermittently confused and had transient loss of central vision. Serum urea and creatinine rose (17.9 mmol/l and 147 µmol/l), haemoglobin fell (8.7 g/dl), and he remained thrombocytopenic (platelets 50x109/l). Urine microscopy revealed 250x106 red blood cells, 30x106 white cells but no casts and no growth on culture. Creatinine clearance was 53 ml/min and 24 h urinary protein excretion was 1.7 g/24 h. Serum C-reactive protein was raised (74 mg/l), and complement C3 and C4 were both low (0.52 and 0.10 g/l). The ESR was 108 mm/h. There was a polyclonal increase in immunoglobulins. Serum iron (1.7 µmol/l), transferrin (1.67 g/l) and total iron binding capacity (42 µmol/l) were all reduced, and iron saturation was only 4%.

Repeat blood cultures, a throat swab, antistreptolysin titres, cryoglobulins and cold agglutinins were all negative, as was screening for dsDNA and other autoantibodies (including lupus anticoagulant and antiphospholipid antibodies), ANCA and anti-glomerular basement membrane (GBM) antibodies. There was no evidence of disseminated intravascular coagulation, with normal prothrombin time, thrombin time, d-dimers and fibrinogen levels. However, the platelet count remained low for 3 weeks. Bleeding time was mildly prolonged (10.5 min), as was the APTT (50.1 s).

Renal biopsy showed that the glomeruli (20) varied from almost normal to florid proliferative (predominantly mesangial and intracapillary) and necrotizing lesions, but with no crescents. There was no splitting of the GBM. With the most severe glomerular damage, there were arteriolar lesions with luminal thrombosis, but no mural necrosis. The tubules contained fibrinoid granular casts and haemolysed red blood cells. There was interstitial oedema and focal acute inflammatory cells. Immunofluorescence was positive for immunoglobulins IgG, IgA and IgM in short segments as a finely granular deposition in the capillary tufts, with fibrinogen-positive material in both the blood vessels and glomeruli. A skin biopsy showed leukocytoclastic vasculitis. The deeper vessels were not involved and immunofluorescence was negative.

Extensive screening showed only IgM antibodies against parvovirus B19 by enzyme-linked immunosorbent assay and radioimmunoassay. No prednisolone, immunosuppression or plasma exchange was given. Nevertheless, there was a steady improvement with symptomatic support only. After 3 weeks, he was able to sit up and walk unaided, and by 7 months he was back at work. All indices of deranged renal, haematological and immunological function had returned to normal, but he continued to need hypotensive medication.



   Discussion
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 Introduction
 Case
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Human parvovirus B19 is a small unenveloped DNA virus comprised of three structural polypeptides and a single-stranded DNA genome core [4]. Infection in adults recently has been associated with sickle cell glomerulonephritis [1], systemic lupus nephritis, chronic arthropathies [2] and systemic necrotizing vasculitis [3]. However, there have been no previous reports, to our knowledge, of HUS following human parvovirus infection in a previously fit man.

Our patient had a complicated story, in keeping with the non-specific symptoms of many viral infections followed by a second phase of more specific system involvement. The blotchy maculo-papular skin rash was typical of parvovirus infection, and indeed is very unusual with HUS. Parvovirus infection can lead to a profound depletion of bone marrow precursors, as in patients with chronic haemolytic anaemias [4].

A blood film had not been examined on presentation, but the kidney biopsy together with the prolonged thrombocytopenia led to a diagnosis of HUS. HUS (and thrombotic thrombocytopenic purpura) encompass a broad, multisystem clinical spectrum accompanied by laboratory evidence of intravascular haemolysis, renal impairment and glomerular fibrin deposition [5]. Our patient had polyarthralgia, abdominal and testicular pain, skin rashes, fluctuating neurological abnormalities, renal failure, thrombocytopenia and haemolytic anaemia. There was also hypocomplementaemia, which can occur in 50% of patients with HUS [6], and with human parvovirus infection [2]. Although the bleeding time is often abnormal in HUS, the clotting profile typically is almost normal [5].

Although endothelial dysfunction and injury is central in the pathogenesis of HUS, many questions remain unresolved [5,7]. Human parvovirus, by contrast, is known to be host-specific and requires dividing cells for its replication and thus targets especially the gastrointestinal, fetal, haematological and lymphoid tissue [2]. The renal damage could arise from both intracapillary thrombosis and immune complex deposition.

There was a temptation to use more aggressive treatment, especially considering the gravity of the illness. However, our patient responded to symptomatic support only. The diagnosis of human parvovirus infection in adults requires a high index of suspicion, and can be missed as IgM positivity lasts only 2–10 weeks in most patients [2]. We recommend early expert advice in these circumstances.



   References
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 Introduction
 Case
 Discussion
 References
 

  1. Wierenga KJJ, Pattison JR, Brink N et al. Glomerulonephritis after human parvovirus infection in homozygous sickle-cell disease. Lancet 1995; 346: 475–476[ISI][Medline]
  2. Fawaz-Estrup F. Human parvovirus infection: rheumatic manifestations, angioedema, C1 esterase inhibitor deficiency, ANA positivity, and possible onset of systemic lupus erythematosus. J Rheumatol 1996; 23: 1180–1185[ISI][Medline]
  3. Finkel TH, Török TJ, Ferguson PJ et al. Chronic parvovirus B19 infection and systemic necrotizing vasculitis. Opportunistic infection or aetiological agent? Lancet 1994; 343: 1255–1258[ISI][Medline]
  4. Anderson MJ. Parvoviruses as agents of human disease. Prog Med Virol 1987; 34: 55–69[ISI][Medline]
  5. Neild GH. Haemolytic uremic syndrome/thrombotic thrombocytopenic purpura: pathophysiology and treatment. Kidney Int 1998; 53 [Suppl 64]: S45–S49
  6. Hebert LA, Cosio FG, Neff JC. Diagnostic significance of hypocomplementaemia. Kidney Int 1991; 39: 811[ISI][Medline]
  7. Remuzzi G, Ruggenenti P. The hemolytic uremic syndrome. Kidney Int 1998; 53 [Suppl 66]: S54–S57[ISI]
Received for publication: 26. 6.98
Accepted in revised form: 28. 5.99





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