Campylobacter-Associated Hemolytic Uremic Syndrome Associated with Pulmonary-Renal Syndrome

Hemolytic uremic syndrome (HUS) is a triad of microangio- pathic hemolytic anemia, thrombocytopenia, and acute kidney injury.2. It typically affects children, with 90 % of cases following gastroenteritis secondary to Shiga toxin (Stx)-producing Escherichia coli 3. Stx-producing Shigella dysenteriae and Campylobacter jejuni have also been linked to diarrhea-associated HUS (D+HUS). 2,4 D + H U Si sm u c hm o r ec o m m o ni nc h i l d r e nt h a na d u l t s , due to high expression of Stx receptors in their renal glomeruli. 5 Therefore, adult cases tend to be sporadic or in association with outbreaks of E.coli infection, such as that reported in Germany in 2011. 6 Adult D+HUS is thought to have the same etiology and pathogenesis as childhood D+HUS, but is more likely to have severe clinical sequelae; such as chronic proteinuria, hyperten- sion, end-stage renal failure and higher mortality rates. 7,8 Campylobacter jejuniinfection is usually a self-limiting gastroenteritis, but in rare cases it can cause post- infectious complications including D+ HUS, uveitis and endocarditis. Most notable is its association with Guillian-Barré Syndrome (GBS); it is a well-described trigger for GBS, with 30 % of cases being preceded by an infection with the pathogen. The immunogenicity of C. jejuni is further apparent in individuals with HLA- B27 antigen who are pre-disposed to a reactive arthritis in the weeks following infection. Given that both con- ditions are observed after an interval of a few weeks from initial infection, it is hypothesized that immuno- logic cross-reactivity such as molecular mimicry is in- volved. 4,9 In our patient, there was an interval between initial infection with Campylobacter jejuni and Table 1. Summary of Laboratory Values at Initial Presentation, Discharge and at Re-presentation Investigation (units) Presentation Discharge Re-presentation Hemoglobin (g/dL) 7.2 12.6 7.1 Platelets (x10 9/L) 25 311 208 Creatinine (mg/dL) 4.98 2.87 3.94 Urea (mg/dL) 97.5 30.2 58.8 Bicarbonate (mmol/L) 14 22 18 Bilirubin (mg/dL) 1.9 1.3 2.5 LDH (iu/L) 873 255 665 Albumin (g/dL) 3.2 3.1 2.8 CRP (mg/L) 60 <2 223 CRP C-reactive protein, LDH lactate dehydrogenase Figure 1. CT pulmonary angiogram showing bilateral ground glass opacities throughout both lungs and peri-bronchovascular consoli- dation mainly within the lower lobes bilaterally; consistent with pulmonary hemorrhage. 354 Bowen et al.: HUS with Pulmonary Renal Syndrome JGIM subsequent development of pulmonary hemorrhage. We hypothesize that the pulmonary-renal syndrome de- scribed in our case report was driven by an immuno- logical reaction to Campylobacter. Our case is unique as it is the first describing pulmonary hemorrhage in association with D+HUS in an adult. There is one previous report of HUS presenting with pulmonary hem- orrhage in an adolescent man in Spain that proved fatal. 10 Piastra et al. described a case of pulmonary hemorrhage in association with typical HUS in a 20-month-old child in 2004. The patient required peritoneal dialysis, invasive ventilation for acute respiratory distress syndrome (ARDS) and was treat- ed with high dose methylprednisolone. Despite pulmonary complications, the HUS showed a benign course following steroid treatment with no residual renal impairment. 11 Pulmonary hemorrhage in association with atypical HUS sec- ondary to mitomycin C chemotherapy in two adult women has been reported by Torra et al. 12. This is thought to be due to angiomatoid vascular changes within the lungs and is likely to represent a pathological process different from that observed in our patient with typical D+ HUS 13. Pulmonary-renal syndrome occurs in anti-GBM disease, ANCA positive vasculitis and systemic lupus erythematosus. In our patient, ANCA, ANA and anti-GBM antibodies were negative at both initial presentation and at re-presentation. Of note, complement levels were normal, excluding factor H deficiency as a cause. Factor H has been identified as a key plasma protein involved in activation of the complement cas- cade via the alternative pathway. Deficiency in factor H is known to result in recurrent infections, membranoproliferative glomerulonephritis type 2 and HUS. Factor H gene mutations are associated with HUS in 20 % of familial cases and 8 % of sporadic cases. It is vital to exclude factor H deficiency as a cause of HUS because risk of recurrence after kidney trans- plantation (resulting in subsequent graft failure) approaches 80 %. 14,15 It is well accepted that HUS results in loss of capillary integrity in the kidney; but it remains unclear as to why this rarely manifests clinically in the lungs. Given the rarity of pulmonary hemorrhage as a complication of D+ HUS, it is difficult to draw conclusions regarding pathogene- sis. However, given that this is the second case of typical D+ HUS with pulmonary hemorrhage that has responded to ste- roid treatment, an immunological mechanism is quite likely. It is clearly impossible to prove the link between the isolat- ed Campylobacter jejuni and the subsequent development of pulmonary hemorrhage, but in the absence of any other cause and the strong temporal relationship in an otherwise complete- ly healthy young woman makes this plausible. It is also Figure 2. a: Renal biopsy (haematoxylin and eosin stain) photomicrographs showing mesangiolytic changes and marked vascular changes with virtual obliteration of some arterioles. b: Silver stain showing double contours of the glomerular basement membrane, resembling a membrano-proliferative architecture. 355Bowen et al.: HUS with Pulmonary Renal SyndromeJGIM impossible to prove that the high-dose steroid therapy reversed this disease process, but the almost immediate improvement in a patient who was showing life-threatening and worsening respiratory compromise for several days is very persuasive. In conclusion, we feel that if pulmonary hemorrhage compli- cates a case of Campylobacter-induced HUS, then high-dose intravenous steroids should be urgently administered, and may be life saving.

Contributors:No other contributors other than the listed authors. Funding: No financial support has been received for the work repre- sented in this manuscript. Conflict of Interest: The authors declare that they do not have a conflict of interest. Corresponding Author: Emily Elizabeth Bowen, M.R.C.P .; Department of Nephrology, King ’s College Hospital, Denmark Hill, SE5 9RS London, UK (e-mail: [email protected]).

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