Safety issues in vasculitis: Infections and immunizations in the immunosuppressed host

Aspergillus species

Another emerging pathogen is Aspergillus species—a ubiquitous mold spread by aerosols of spores. There are many different species of Aspergillus, but the most common human pathogens include A fumigates, A niger, and A flavus. To date, 39 cases of Aspergillus infection associated with infliximab and etanercept have been reported in the Adverse Event Reporting System, translating to 9 to 12 cases per 100,000 patients.²¹

Manifestations of the various types of Aspergillus infection include invasive pulmonary aspergillosis, which is classically a cavitary disease with a halo effect; chronic necrotizing pneumonia, which has no specific identifying characteristics; and disseminated CNS aspergillosis, causing abscesses in immunosuppressed patients (Figure 3).

Varicella zoster

Herpes zoster infection is caused by reactivation of latent infection. In the United States, 95% of adults are seropositive for herpes zoster with a 10% to 30% lifetime risk of zoster reactivation.³² It is the most common viral infection in multiple series of patients with connective tissue diseases. In a multivariate analysis by Wolfe et al³³ of patients with RA, cyclophosphamide (hazard ratio [HR] 4.2), azathioprine (HR 2.0), and prednisone (HR 1.5) were significant predictors of herpes zoster. TNF inhibitor risk (HR 1.82) is less clear, with studies demonstrating no definitively increased risk. Manifestations of herpes zoster include localized disease (thoracic zoster as the most common presentation), disseminated cutaneous zoster, and disseminated visceral zoster (with encephalitis, myelitis, and angiitis) (Figure 4).

JC virus

More than 80% of adults are seropositive for JCV, a DNA virus of the genus Polyomavirus that causes lytic infection of oligodendrocytes.³⁴ In immunocompromised hosts, JCV causes progressive multifocal leukoencephalopathy (PML), a rare but devastating demyelinating disease. PML was first described in malignancy, leukemia, and various other immunocompromised states, prior to its strong association with AIDS in the 1980s. More recently, JCV has been associated with natalizumab for multiple sclerosis and Crohn disease, rituximab for oncology patients, efalizumab for psoriasis,³⁵ and mycophenolate mofetil for transplant recipients.³⁶

In 2006 the US Food and Drug Administration issued a safety alert regarding PML in two patients with SLE treated with rituximab and other immunosuppressives.³⁷ In a review of PML in rheumatic disease, 36 cases were identified in patients who had not previously received a biologic agent. Most of these patients (60%) had SLE.³⁸ Of these, many had little or no immunosuppression over the 6 months prior to the diagnosis of PML, suggesting that SLE itself may predispose to PML. Interestingly, PML is rarely associated with TNF inhibitors.

Classic presentation of PML includes motor weakness, aphasia, dysarthria, vision loss, and cognitive loss. Atypical presentation includes seizures, headaches, and brainstem involvement. PML usually spares the optic nerves, spinal cord, peripheral nerves, and muscles. In persons with underlying rheumatic diseases, PML can be difficult to distinguish from neuropsychiatric SLE or CNS vasculitis.

Diagnosis. On magnetic resonance imaging, typical presentation of PML shows T2 and fluid attenuated inversion recovery hyperintense regions in the white matter, asymmetric parietal and occipital radiations, and occasional cerebellum and basal ganglia involvement (Figure 5). If magnetic resonance imaging is normal, PML usually can be excluded. Cerebrospinal fluid examination shows a mean of 7 white blood cells/μL. PCR for JCV in cerebrospinal fluid has a specificity of close to 100% in persons with advanced HIV based on data prior to the use of highly active antiretroviral therapy.³⁹ Sensitivity using older assays is approximately 70% to 90% while the sensitivity of newer quantitative “ultrasensitive” PCR assays is greater than 90%.^40,41

Treatment. In clinical trials no antiviral agent has been effective in the treatment of PML. In HIV patients who develop PML, highly active antiretroviral therapy should be initiated (if antiretroviral-naïve) or existing antiviral regimens optimized. Antiretroviral therapy in this situation may stabilize disease and possibly increase survival.⁴² For HIV-negative patients who develop PML, the cornerstone of management is immediate decrease or discontinuation of immunosuppression.⁴³ Several adjunctive measures have been reported mainly in natalizumab-associated PML, including corticosteroids, mirtazapine, plasma exchange, and others.

VACCINES

Vaccination is important in the prevention of infectious disease in immunocompromised patients with connective tissue diseases. Because live vaccines are contraindicated in immunocompromised patients, inactivated or component vaccines should be used. It is recommended that patients who will start immunosuppressive therapy be vaccinated 2 to 4 weeks before beginning therapy. If this is not possible, vaccination should be administered during disease remission, 3 months after immunosuppression and 1 to 3 months after administration of high-dose corticosteroids.

Table 1 lists common live (attenuated) vaccines and inactivated vaccines. Live influenza vaccine is available as a nasal spray, but that route of administration is contraindicated in immunocompromised patients and those aged over 50 years. To further define the contraindications in immunocompromised patients, corticosteroids are not a contraindication to live-virus vaccines when corticosteroid administration is:

• Short-term (less than 14 days)
• At a dose of less than 20 mg/day of prednisone or equivalent
• Long-term on alternate days with short-acting preparations
• At a physiologic dose of prednisone
• Topical, inhaled, intra-articular, bursal, or via tendon.⁴⁴

No data are available to guide immunization while a patient is taking anti-TNF agents, but the Centers for Disease Control and Prevention (CDC) recommend “caution in the use of live vaccines” with these drugs with “avoidance” unless the benefit, by case, greatly outweighs the risk.⁴⁴ Similarly, there are no data on vaccine safety or specific recommendations with rituximab treatment. However, following the recommendations for “functional asplenia” in the CDC guidelines, pneumococcal, meningococcal, and Haemophilus influenzae type b (Hib) vaccine (if not given in infancy) would be indicated. Table 2 summarizes the CDC recommendations for vaccinating immunocompromised adults (excluding those with HIV).

Until definitive guidelines are developed, practitioners must evaluate and treat each patient individually to maximize the efficacy of disease treatments while preventing infection morbidity and mortality in their patients with connective tissue diseases.