Cryoglobulinaemic vasculitis caused by intravenous immunoglobulin treatment

Jonathan Odum,1, Dominic D'Costa2, Mark Freeth3, David Taylor4, Neil Smith5 and Alan MacWhannell5

1 Departments of Renal Medicine 2 General Medicine and 3 Histopathology 4 Dermatology 5 Haematology, New Cross Hospital, Wolverhampton, UK

Keywords: cryoglobulinaemia; glomerulonephritis; immunoglobulin; vasculitis



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
Intravenous immunoglobulin (IVIG) is used as replacement treatment for patients with hypogammaglobulinaemic states (both primary and secondary), and due to its immunomodulatory properties is also used to treat certain autoimmune or inflammatory conditions (idiopathic thrombocytopenia purpura, Guillain–Barre syndrome, dermatomyositis, Kawasaki disease). Generally, administration of IVIG is safe, and although the incidence of reported side-effects ranges from 5–15%, these are usually mild and comprise pyrexia, headache, malaise and rash [1,2]. More rarely, serious life-threatening adverse reactions may occur including anaphylaxis (particularly in patients with IgA deficiency) [1] and acute renal failure [3]. Indeed, with respect to the latter, a recent editorial [4] has reviewed the available data regarding IVIG-associated renal impairment and has suggested that in most cases the cause is non-glomerular, but rather is secondary to proximal tubular ‘toxicity’.

In this report, we present a patient who developed cutaneous cryoglobulinaemic vasculitis, thrombocytopenia and presumed glomerulonephritis following IVIG therapy for treatment of Guillain–Barre syndrome (GBS).



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A previously fit 59-year-old woman was admitted with progressive weakness affecting both arms and legs following 2 days of influenza-type symptoms. Clinical examination revealed a flaccid tetraplegia (1/5 weakness distally, 3/5 weakness proximally) and areflexia. A clinical diagnosis of GBS was made and because of a progressive decline in capillary oxygen saturation and tidal volume she was transferred to the intensive care unit where she required endo-tracheal intubation and ventilation 6 h after her initial admission. In accordance with local policy regarding the treatment of GBS, she was commenced on IVIG (Vigam-S®) infusions 25 g (0.4 g/kg bodyweight) once daily for 5 days. Forty-eight hours after starting IVIG, a petechial rash developed across her trunk and flexor surfaces, and in association with this there was a progressive fall in platelet count and rise in plasma creatinine (Figure 1Go). Dipstick urinalysis revealed 4+ blood and 3+ proteinuria. Renal biopsy was not performed because of the thrombocytopenia. Hydrocortisone 100 mg was given four times on day 3 and i.v. methylprednisolone 500 mg was given daily on days 5 and 6, following which there was improvement in both renal function and the cutaneous lesions.



View larger version (17K):
[in this window]
[in a new window]
 
Fig. 1. Clinical course of the patient following admission. HC 1004, hydrocortisone 100 mg four times daily; PE, plasma exchange; MP, methylprednisolone.

 
Further investigations revealed the following results: antineutrophil cytoplasmic antibodies (ANCA) and ANA negative; RF 53 IU/ml (0–20); plasma complement components C3 0.24 g/l (0.75–1.65) and C4 0.05 g/l (0.2–0.65). Plasma immunoglobulin concentrations immediately following admission were not able to be quantified as blood had been collected under normal conditions and on analysis in the laboratory it was evident that the sample contained a cryoprecipitate. However, further analysis of the first sample revealed the cryoprecipitate to contain polyclonal IgG and monoclonal IgM {kappa}. Therefore a further serum sample was collected at 37°C on day 8 and plasma immunoglobulins were quantified at 37°C. However, this sample was taken after the administration of the IVIG and thus the immunoglobulin concentrations would not necessarily have been representative of the immunoglobulin concentrations on admission (particularly the IgG concentration). Nevertheless, the concentrations of the immunoglobulins in this sample were as follows: IgG 9.5 g/l (5.3–16.5), IgA 0.63 g/l (0.8–4.0) and plasma immunoelectrophoresis revealed two paraprotein bands typed as IgM {kappa} and IgM {lambda} quantified at 15.3 g/l. Cryoglobulins were detected in the plasma, the cryoprecipitate containing monoclonal IgM {kappa} and polyclonal IgG. Subsequent examination of bone marrow showed infiltration by low-grade non-Hodgkin's lymphoma with cell surface marker analysis demonstrating that 50% of lymphocytes were of neoplastic B-cell origin, expressing CD19, CD20, CD22, FMC7, CD11c and kappa. With these results, a diagnosis of cutaneous vasculitis and glomerulonephritis secondary to cryoglobulinaemia was made and a further dose of i.v. methylprednisolone 500 mg given on day 9. In addition, the diagnosis of GBS was critically reassessed. Examination of cerebro-spinal fluid revealed no abnormality and nerve conduction studies were inconclusive. We therefore considered whether the neurological presentation may have been related to hyperviscosity syndrome or possibly secondary to a paraprotein-related neuropathy. Accordingly, blood was sent for asesssment of plasma viscoscity and for the presence of antibody markers for monoclonal antibody-associated neuropathy. As there was to be a delay in the results of these tests becoming available, a decision was made to commence plasma exchange (PE) empirically, pending these further results. The patient was given 3 l PE daily for 3 days, commencing on day 12. The replacement fluid used was 4.5% albumin. Subsequently, plasma viscosity performed at 37°C on day 12 (prior to the plasma exchange) returned as 1.38 (normal) and anti-glycolipid antibody status was negative (antibodies to GM1, asialo-GM1, GD1a and -b), indicating that she did not have a paraprotein-associated neuropathy. In addition, microbiological culture of the patient's stool had grown campylobacter and we ultimately concluded that the patient's original presentation was due to GBS.

By day 15 the patients clinical condition had deteriorated and she had become pyrexial with pneumonia. As the pneumonia had occurred whilst undergoing a course of plasma exchange, this was discontinued after the third exchange, and in view of the severity of the infection and the possibility that this might be exacerbated by IgG depletion, it was decided to give her further treatment with IVIG as replacement therapy. Accordingly, pooled human immunoglobulin was given i.v. as replacement therapy once daily for a further 5 days (days 15–19). Blood was again taken at 37°C to assess immunoglobulin concentration following the plasma exchange but prior to the IVIG administration, and results were subsequently returned and were as follows: IgG 9.8 g/l; IgA 0.47 g/l; IgM 5.02 g/l; IgM paraprotein concentration 4.1 g/l. On this occasion the IVIG used for the first 3 days (days 15–17) was Vigam-S (20 g/day). However, Sandoglobulin 34 g daily was given for the last 2 days (days 18 and 19) as on day 17 a generalized erythematous rash had appeared and concern was raised that the rash represented a reaction to the Vigam-S. However the rash progressed rapidly, such that by day 22 she had a widespread purpuric/vasculitic rash over trunk and limbs (Figure 2Go). In association with this there was a progressive fall in platelet count but no change in plasma creatinine (Figure 1Go). A skin biopsy of one purpuric area was performed, and the histology showed acute vasculitis affecting dermal vessels with plugs of PAS-positive material within the vascular laminae, appearing to be compatible with cryoglobulinaemic vasculitis (Figures 3Go and 4Go). Unfortunately, examination of the biopsy for immunoprecipitants was not possible for technical reasons. On day 22 she was given prednisolone 60 mg orally, and two further doses of methylprednisolone 500 mg were given intravenously on days 24 and 25. Unfortunately, the patient became acutely unwell on day 26, with haemodynamic studies suggesting septicaemic shock from which she died a few hours later. At the family's request an autopsy was not performed.



View larger version (137K):
[in this window]
[in a new window]
 
Fig. 2. Widespread confluent purpuric/petechial rash affecting the trunk. The same rash was present over the four limbs.

 


View larger version (132K):
[in this window]
[in a new window]
 
Fig. 3. Low-power photomicrograph of skin biopsy illustrating plugging of dermal vessels with PAS-positive material.

 


View larger version (131K):
[in this window]
[in a new window]
 
Fig. 4. High-power photomicrograph of skin biopsy showing perivascular inflammation with inflammatory cells surrounding and penetrating the wall of a small arteriole. The lumen is plugged by PAS-positive material. The appearence is that of cryoglobulinaemic vasculitis.

 



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
Vasculitis during or following IVIG treatment is rare. However, facial vasculitis [5] and uveitis [6] have both been reported following IVIG administration. In the case of facial vasculitis the aetiology of the reaction was unexplained. In the case of uveitis the authors proposed the presence of ANCA in the IVIG preparation as the cause of the uveitis. However, this assertion was subsequently challenged [7].

Our case report describes the development of cutaneous cryoglobulinaemic vasculitis and presumed glomerulonephritis following IVIG administration given as therapy for GBS. The diagnosis of GBS was presumed in view of the clinical presentation, and IVIG commenced empirically. However, following the diagnosis of non-Hodgkin's lymphoma and with the knowledge that there was an IgM paraprotein with cryoglobulin activity present in the plasma, the diagnosis of GBS was critically reassessed. However, the patient's plasma was not hyperviscous and the characteristic antibodies of a monoclonal antibody-associated neuropathy were not present. Moreover, the presence of campylobacter in the faeces coupled with the clinical picture (despite the normal CSF findings) led us to presume that GBS was the correct diagnosis. Furthermore, it is possible that the patient was IgG deficient prior to and at presentation, hence predisposing her to the campylobacter infection. Unfortunately, the presence of the unsuspected cryoglobulins on admission (and hence blood being taken under the wrong conditions) resulted in the first accurate plasma IgG quantification being made after the IVIG infusion was given and may therefore not be representative of the IgG concentration on admission. However, at the time of the IVIG treatment the patient had an unsuspected and undiagnosed B-cell lymphoma associated with two IgM paraprotein bands ({kappa} and {lambda}) with rheumatoid factor activity. Presumably, the administration of exogenous polyvalent IgG provoked the formation and subsequent precipitation of IgM–IgG (monoclonal IgM and polyclonal IgG) immune complexes, with consequent cutaneous vasculitis and glomerulonephritis. The clinical manifestations following the first course of IVIG were not severe, with the exception of the thrombocytopenia, and responded to steroid treatment. Neither skin biopsy nor renal biopsy was performed initially, particularly in view of the thrombocytopenia. However, the rise in plasma creatinine associated with the presence of heavy microhaematuria and proteinuria on dipstick urinalysis indicated the probable presence of a glomerulonephritis. At the time of the first apparent complication from the IVIG it was not recognized that this was related to cryoprecipitation of monoclonal IgM {kappa} with the exogenously administered polyvalent IgG (IVIG) as this appears to be a very rare event, occurring only in certain circumstances (see below). The second course of IVIG was therefore given as replacement treatment empirically to the patient who had developed a serious pneumonia during the short course of plasma exchange, which it was thought may have made her IgG deficient. As it transpired, the patient's plasma IgG concentration immediately following the plasma exchange was normal; however this was not known at the time of IVIG administration. However, following the second course of IVIG (given as replacement therapy) a florid cutaneous vasculitis developed, the histological features of which were those of cryoglobulinaemic vasculitis.

To our knowledge, only one previous report has documented the development of cryoglobulinaemic glomerulonephritis following IVIG treatment in a patient with B-cell lymphoma and a pre-existing IgM {kappa} paraprotein [8]. The authors suggested that IVIG should not be given to patients with B-cell lymphoma and IgM paraprotein in view of the potential complication. The clinical features of our case would tend to confirm this observation.

The cause of the profound thrombocytopenia was unclear but was presumed secondary to peripheral destruction/removal of platelets in the presence of high circulating plasma immune-complexes. Reduction in platelet count following IVIG infusion is an otherwise uncommon phenomenon.

In summary, we have described cryoglobulinaemic vasculitis secondary to IVIG treatment in a patient with a pre-existing IgM {kappa} paraprotein with rheumatoid factor activity. The clinical observations in our patient are similar in many ways to those made by Barton et al. [8] and confirm the potential dangers in giving such patients IVIG. Although such patients are rare, at the very least we would advise caution in considering the need for IVIG for patients with IgM paraproteinaemias.



   Notes
 
Correspondence and offprint requests to: Dr Jonathan Odum, Renal Unit, New Cross Hospital, Wolverhampton WV10 0QP, UK. Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Yap PL, Williams PE. The safety of IVIG preparations. In: Yap PL, ed. Clinical Implications of Intravenous Immunoglobulin Therapy. Churchill Livingstone. 43–62
  2. Schifferli JA. Adverse effects of intravenous immunoglobulin. Transfus Sci1992; 13: 331–338[ISI]
  3. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol1997; 8: 1788–1794[Abstract]
  4. Stahl S, Schifferli JA. The renal risks of high-dose intravenous immunoglobulin treatment. Nephrol Dial Transplant1998; 13: 2182–2185[Free Full Text]
  5. Howse M, Bindoff I, Carmichael A. Facial vasculitic rash associated with intravenous immunoglobulin. BMJ1998; 317: 1291[Free Full Text]
  6. Ayliffe W, Haeney M, Roberts SC, Lavin M. Uveitis after antineutrophil cytoplasmic antibody contamination of immunoglobulin replacement therapy. Lancet1992; 339: 558–559 (letter)[Medline]
  7. Donatini B, Goetz J, Hauptmann G. Uveitis and antineutrophil cytoplasmic antibody in immunoglobulin batches. Lancet1992; 339: 1175–1176 (letter)[ISI][Medline]
  8. Barton JC, Herrera GA, Galla JH, Bertoli JF, Work J, Koopman WJ. Acute cryoglobulinaemic renal failure after intravenous infusion of gamma globulin. Am J Med1987; 82: 624–629[ISI][Medline]
Received for publication: 10. 2.99
Revision received 26. 9.00.