The Next Outbreak Looms on the Horizon: Measles and Potential Impacts on Transplant Recipients

Significant outbreaks of measles are occurring throughout the world, including the United States, the United Kingdom, India, and other areas with significant rates of organ transplantation, fed in part by vaccine reluctance and lower rates of childhood vaccination.1,2 Measles is transmitted via airborne spread or respiratory droplets and is among the most contagious of pathogens with infection occurring in up to 90% of nonimmune close contacts3; a single case of infection is estimated to cause 12–18 secondary cases in susceptible individuals1,4 and may be even more contagious in susceptible immunocompromised populations. Measles typically presents with fever, maculopapular rash, conjunctivitis, cough, and coryza, although such symptoms may be muted in transplant recipients, who may present without a rash.5,6 Serious manifestations of the disease include pneumonia due to measles virus or superimposed secondary infection and acute disseminated encephalomyelitis, a demyelinating disease of the central nervous system that develops in 1:1000 cases.5 There is no effective antiviral treatment for measles and the management is supportive.5 Beyond the acute mortality, long-term sequelae also contribute to morbidity and delayed mortality: disability related to permanent brain damage from acute encephalomyelitis; measles inclusion body encephalitis, which occurs typically in immunocompromised individuals 6–12 mo after infection; and subacute sclerosing panencephalitis, a fatal progressive neurodegenerative disease that occurs years later in roughly 1:10 000 of cases.1,5,7 Rates and outcomes in immunocompromised patients are largely unstudied; as with so many other infections, they are likely at higher risk for severe outcomes.6 Before the measles vaccine became licensed in 1963, it was estimated that 3–4 million people in the United States were infected annually, resulting in an average of 48 000 hospitalizations, 1000 people with chronic disability from acute encephalitis, and 500 deaths annually.1 The Centers for Disease Control and Prevention (CDC) considers individuals born before 1957 as immune to measles as they were almost certainly infected during childhood.8 After measles outbreaks in school-aged children, a second dose of measles, mumps, and rubella (MMR) vaccine was recommended for all children in 1989. Effective vaccination for measles dramatically changed the landscape of the disease and measles was announced as eliminated in the United States in 2000.1 Recent outbreaks put immunocompromised individuals such as transplant recipients at high risk for developing measles, especially those with waning or no immunity. The majority of current transplant recipients in the United States were born after 1957 and before the late 1970s, the cohort at highest risk for poor protection from prior vaccine per the CDC as they are less likely to have been infected in childhood and may have only had a single dose of vaccine, which provides inadequate protection and led to outbreaks of disease.9-12 In a series from Houston, 20% of transplant candidates were measles seronegative before transplant, whereas in a series of 672 transplant candidates from Salt Lake City, 13% were measles seronegative.13,14 In combination with immunosuppression, this makes transplant recipients exceptionally vulnerable to measles. Vaccination is the best way to protect against measles. The measles live attenuated viral vaccine is not available as a monovalent measles vaccine in the United States or Canada but is available as part of a combination vaccine for MMR, which is highly effective against measles with studies showing >90% seroconversion rates and low waning immunity.1,15 Therefore, the CDC states that either documentation of at least 1 dose of measles vaccine (2 doses for those at higher risk) and/or laboratory evidence of immunity or being born before 1957 to be considered sufficient protection.8 Unfortunately, the MMR vaccine is not recommended for adult transplant recipients (Table 1) as live viral vaccines can cause illnesses such as measles pneumonitis, meningitis, and encephalitis in immunocompromised individuals.7,16 This is highly problematic as the most vulnerable individuals are unable to get the most effective preventive strategy. A recent study of live vaccination of 281 pediatric solid organ transplant recipients showed no cases of measles after the MMR vaccine, raising questions about whether we should reconsider the safety of live vaccination in pediatric transplant recipients. It is important to note the study included a highly selected group of participants with a median age of 8.9 y (interquartile range, 4.7–13.8 y), median time since transplantation of 6.3 y, 96% were liver transplant recipients, and 73% were on low-level immunosuppression, consisting of monotherapy with either tacrolimus, sirolimus, or cyclosporine dosed for trough level goals of <5, 5, and 100 ng/mL, respectively.17 Therefore, the findings cannot be generalized to transplant recipients outside the inclusion criteria of the study. The safety of live vaccination has not been demonstrated in immunocompromised older adults, who are the ones at higher risk of being nonimmune to measles. TABLE 1. - Prevention of measles in transplant candidates and recipients through vaccination and immunoglobulin Strategy Dosing Advantages Comments MMR vaccination Two doses given at least 4 wk apart Most effective prevention strategy Recommended only before transplantation in adults due to risk of live vaccine-associated disease(s) May be safe in pediatric recipients on lower immunosuppression A minimum of 4 wk should separate the last vaccine dose from immunosuppression for transplantation Intravenous immunoglobulin postexposure prophylaxis One dose of 400 mg/kg given within 6 d of exposure Rapid protection, safe for transplant recipients (and candidates) on immunosuppression who cannot get MMR vaccine Lack of high-quality data demonstrating effectiveness in transplant recipients Different formulations and batches may have different amounts of anti-measles antibodies Expensive, cumbersome, and has potential side effects Protects short term but not longer term Intramuscular immunoglobulin postexposure prophylaxis One dose of 0.5 mL/kg (maximum dose = 15 mL) Based on the Centers for Disease Control and Prevention. Recommendations. Available at https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6204a1.htm. Accessed March 3, 2024 and the Infectious Disease Society of America. Accessed March 3, 2024; Rubin LG, Levin MJ, Ljungman P, et al: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58:e44–e100.MMR, measles, mumps, and rubella. Therefore, transplant programs should ensure that transplant candidates are well vaccinated against measles before transplantation and the initiation of immunosuppressive medications. Furthermore, transplant programs should not transplant organs from donors with a recent measles infection or known exposure, given the potential risk of transmission and lack of antiviral therapies.18 Beyond transplant programs, the onus is also on immunocompetent individuals to get vaccinated to achieve community immunity and form “vaccine circles” that protect their contacts who are immunocompromised, adding another layer of prevention. Given its high transmissibility, it is estimated that vaccination of ≥95% of the eligible population is needed to obtain enough community immunity to eliminate measles.5 Another prevention strategy is the administration of immunoglobulins for postexposure prophylaxis, which the CDC recommends for severely immunocompromised individuals within 6 d of exposure to measles.1 For those at high risk of exposure in outbreaks, pre-exposure prophylaxis with immunoglobulins might be efficacious, although would be expensive, cumbersome to administer, and have potential side effects. Another factor that may affect the effectiveness of postexposure prophylaxis is that there are significant variations in the levels of anti-measles antibodies between different immunoglobulin preparations and even within different batches of the same immunoglobulin preparation.19 Therefore, the effectiveness of measles postexposure prophylaxis with intravenous or intramuscular immunoglobulin in immunocompromised individuals requires further study. Lastly, very limited data from in vitro measles virus dissemination assays suggest that other antiviral agents, specifically remdesivir, may have a role in postexposure prophylaxis or treatment, but this requires rigorous study in animal models and humans.20 In summary, the current measles outbreaks are very concerning and harbingers of worse disease activity ahead. We call on government agencies, pharmaceutical companies, and transplant programs to enhance vaccination rates where possible, and advance research in the realm of prevention via immunoglobulins and treatment options. Without achieving robust individual and community immunity through vaccination, we put immunocompromised individuals at high risk for serious, debilitating, and even deadly complications from this terrible and highly preventable disease.

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