Systemic Inflammatory Reaction to Intravitreal Bevacizumab: A Case Report


 IntroductionTo present a case of systemic inflammatory reaction, with associated pleural and pericardial effusions, following intravitreal bevacizumab for retinal macroaneurysm. Case presentationA 73 year old female was commenced on monthly intravitreal bevacizumab injections for right eye macroaneurysm and associated macular oedema. Eight days following her third injection, the patient was admitted to hospital with a history of fever, rigors, arthralgia and vomiting. Admission blood tests demonstrated mild thrombocytopaenia and raised inflammatory markers. A CT chest revealed small pericardial and pleural effusions. The patient improved without treatment and was later discharged from hospital. As intravitreal bevacizumab treatment continued, the patient developed two further episodes of fever and vomiting, with both episodes occurring approximately nine days following each injection. The patient then underwent outpatient medical review by infectious disease and rheumatology specialists, at which time the recurrent episodes of systemic inflammation were diagnosed as secondary to intravitreal bevacizumab.ConclusionsThough rare, patients can develop serious and potentially life-threatening systemic adverse effects from intravitreal anti-VEGF treatment. Ophthalmologists should always enquire about systemic side effects; in this way, adverse effects may be recognised sooner and a change or cessation of therapy considered.


Introduction
Systemic adverse effects from intravitreal anti-vascular endothelial growth factor (VEGF) treatment are rare [1]. However, monoclonal antibodies, as with other exogenous proteins, are recognised to provoke immuno-in ammatory reactions [2]. We present a case of systemic in ammatory reaction, with associated pleural and pericardial effusions, following intravitreal bevacizumab treatment for retinal macroaneurysm.

Case Presentation
A 73 year old female was referred to a medical retina clinic with an acute decline in vision in her right eye.
The patient's ophthalmic history was signi cant for previous left branch retinal vein occlusion, hypertensive retinopathy, age-related macular degeneration and bilateral mild cataract. Her right eye best corrected visual acuity (BCVA) was recorded as 6/60. A macroaneurysm within the right superotemporal arcade was detected with signi cant surrounding haemorrhage and macular oedema ( Figure 1).
Following informed consent, the patient was commenced on a course of monthly 1.25mg intravitreal bevacizumab injections to the right eye. The macular oedema responded to this anti-VEGF treatment with improvement in central foveal thickness from 479μm to 285μm following three injections, although her BCVA remained 6/60. Eight days following her third bevacizumab injection, the patient was admitted to hospital with a three day history of fever, rigors, arthralgia and vomiting. Admission blood tests demonstrated mild thrombocytopaenia and CRP 22. Autoimmune screening was positive for lupus anticoagulant and borderline positive ANA at 1:320. Routine and atypical infectious disease screens were negative. A CT chest demonstrated small pericardial and pleural effusions with mediastinal lymphadenopathy. The patient was discharged after four days with no further episodes of fever recorded whilst in hospital. No antibiotic or steroid therapy was initiated during her stay.
Following two additional bevacizumab injections and right eye cataract surgery, the patient's right BCVA improved to 6/24. However, two further episodes of fever and vomiting were noted to occur around nine days following both injections. The patient underwent outpatient review by infectious disease and rheumatology specialists. Her recurrent episodes of systemic in ammation and fever were diagnosed as secondary to intravitreal bevacizumab. A change in intravitreal treatment was therefore recommended. At a subsequent ophthalmology appointment, the patient was diagnosed with branch retinal vein occlusion in the same eye and a course of intravitreal a ibercept was initiated. No systemic in ammatory reactions have been noted following a ibercept injections and right BCVA has improved to 6/9.

Conclusions
As a focal dilatation of a retinal arteriole, macroaneurysms typically occur in female hypertensive patients [3]. Observation is appropriate in asymptomatic patients. However, patients may present with an acute deterioration in vision secondary to macular oedema or vitreous haemorrhage [3]. Intravitreal bevacizumab has been shown to improve macroaneurysm-associated macular oedema [4].
Bevacizumab, commonly referred to by its trade name Avastin, is often prescribed off-license in the United Kingdom for macular oedema or neovascularisation, in patients who do not meet funding criteria for a ibercept or ranibizumab. Although anti-VEGF drugs are detectable in the systemic circulation following intravitreal injection, systemic side effects are rare [1,5]. Intravitreal anti-VEGF therapy has been linked to non-ocular haemorrhage, arterial thromboembolic events and systemic infections [1]. The systemic safety pro les of bevacizumab, ranibizumab and a ibercept, the three most commonly prescribed anti-VEGF agents, are not considered to be signi cantly different [1].
Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A) [3]. Other monoclonal antibody therapies are associated with systemic in ammation; this is the result of a hypersensitivity drug reaction and referred to as serum sickness [2]. In these type III hypersensitivity reactions, antibodies develop in response to an antigen, forming antigen-antibody or immune complexes [2]. If the mononuclear phagocyte system is saturated by the immune complex load, excess complexes can form and deposit throughout the body, triggering an in ammatory response and activating the complement system. In this case, although the mechanism of systemic in ammation is likely the result of a bevacizumab hypersensitivity reaction, the patient did not meet criteria for a diagnosis of serum sickness.
Following a change in anti-VEGF therapy from bevacizumab to a ibercept, the patient has not experienced any further in ammatory episodes. A ibercept is a recombinant fusion protein that acts as a decoy receptor for VEGF-A and VEGF-B, as well as binding to placental growth factor [3]. Its different molecular composition to bevacizumab may explain why the patient has not developed an immune response to this drug.
Though rare, this case serves as a reminder that patients can develop serious and potentially lifethreatening systemic adverse effects from intravitreal anti-VEGF treatment. Ophthalmologists should enquire about systemic side effects in patients undergoing anti-VEGF injections. In this way, adverse effects may be recognised sooner and a change or cessation of therapy considered. Figure 1 Right eye fundus photo and OCT macula at time of macroaneurysm diagnosis