Vaccine-Associated Measles in an Immunocompromised Host: Hospital Infection Prevention and Control and Public Health Response

Abstract

Introduction:

Vaccine-associated measles is generally not considered to be transmissible, as opposed to wild-type measles, which is one of the most highly contagious diseases. Data on contact and exposure management of vaccine-associated measles is limited, with varied approaches to such cases described in the literature.

Methods:

We report the case of a 2-year-old immunosuppressed child who developed a febrile exanthem with mild conjunctivitis 18 days after receiving the measles-mumps-rubella-varicella vaccine.

Results:

Given the patient's recent measles-containing vaccination while on immunosuppressive medications, consistent clinical findings, and the lack of epidemiological risk factors for wild-type infection the decision was made to treat this as a presumptive case of vaccine-associated measles virus prior to return of confirmatory genotyping results. After consultation with public health experts, contact tracing was not considered necessary. No secondary measles cases were identified, despite a large exposure potential due to lack of consistent airborne precautions during hospital admission.

Discussion:

This case highlights the lack of transmissibility of vaccine-associated measles in immunocompromised hosts, adding to the scant body of literature on this topic, with the potential to inform hospital infection prevention and control as well as public health management in similar situations.

Case Presentation

A 2-year-old child with trisomy 21 on chronic immunosuppressive treatment with sirolimus monotherapy (target level 5–10) for episodes of hyperinflammation of unclear etiology received the measles-mumps-rubella-varicella (MMRV) vaccine, followed by RSV prophylaxis 11 days later. Twelve days post-MMRV vaccination, the child presented to hospital with a 1-day history of fever and progressive erythematous papular rash. As vesicles were noted, empiric acyclovir was initiated until the lesion swab and blood polymerase chain reaction (PCR) for varicella-zoster virus were negative. The child's hospital admission lasted 6 days, during which time the rash significantly improved. Airborne precautions were adhered to from presentation until varicella was ruled out, 3 hours prior to discharge.

One day after discharge (day 18 post-MMRV vaccination), a new febrile erythematous maculopapular rash developed, initially on the neck and abdomen, spreading to the face, back, and limbs, but sparing the palms and soles. The rash was accompanied by mild conjunctivitis; there was no history of cough or coryza. There was no history of travel, no contact with a person with measles-like symptoms, nor any recent reports of local measles cases. The patient was re-admitted to the hospital and remained in a single patient room throughout, but was not in an airborne infection isolation room, for 1 hour in the emergency department and for 13 1/2 hours while admitted on the general paediatric ward. Typically, there are 6 air changes per hour in non-airborne infection isolation rooms, and 9 to 14 air changes per hour in airborne infection isolation rooms. Additionally, given their age, the patient did not wear a surgical mask while being transported through the hospital.

Serological (blood) and PCR (throat swab and urine) testing were conducted to establish a diagnosis.

Diagnosis

Measles serology resulted IgM reactive and IgG non-reactive; measles was detected by PCR in the urine and throat swab specimens. Ten days later, Canada's National Microbiology Laboratory (NML), a WHO/PAHO Regional Reference Laboratory for measles and rubella, confirmed that the measles virus identified from the patient was genotype A, consistent with vaccine-associated measles (1).

There were no signs of hyperinflammation on bloodwork. Respiratory multiplex nasopharyngeal swab PCR, Chlamydophila/Mycoplasma throat swab PCR, and blood PCRs for adenovirus, enterovirus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV6) all returned negative. Rubella serology resulted IgM reactive and IgG non-reactive, but nasopharyngeal PCR testing returned negative.

Discussion

The case was managed in collaboration with the hospital's infection prevention and control team, the local public health unit, and in consultation with Public Health Ontario. Given the patient's recent measles-containing vaccination while on immunosuppressive medications, consistent clinical findings, and the lack of epidemiological risk factors for wild-type infection, the decision was made to treat this as a presumptive case of vaccine-associated measles virus prior to confirmatory genotyping test results, which can take several weeks. After consultation with public health experts, contact tracing was not considered necessary. Vaccine-associated virus is generally not considered to be transmissible, as opposed to wild-type measles, which is one of the most highly contagious diseases (2, 3, 4). Had this been wild-type measles, the exposure would have been substantial, necessitating resource-intense contact follow-up given the lack of consistent negative pressure room isolation in the emergency department and on the general paediatric ward, with approximately 70 exposed patients. No measles cases were identified in Ontario for more than 3 weeks following the last theoretical transmission opportunity from this patient, assuming the infectious period of wild-type measles.

Viral shedding post-MMRV vaccination is known to occur, with one study showing that most patients had detectable measles vaccine virus RNA for less than 20 days, while one case was detectable up to 784 days post-immunization (5). Despite the detection of measles virus RNA, transmission to close contacts has not been documented (6). The live-attenuated virus in measles vaccines replicates poorly in human tissues while eliciting an immune response that confers long-term protection (7). It is theorized that in cases of vaccine-associated measles, increased viral replication occurs, resulting in a higher viral load than is usually conferred by immunization alone, especially in immunocompromised patients who might have impaired viral clearance (7).

Cases of vaccine-associated measles do not meet the surveillance case definition for measles in Canada but are reportable to public health as an adverse event following immunization (AEFI) when they occur between 5 and 42 days after vaccination (8) with vaccine-strain genotype confirmed by Canada's NML. Severe adverse events such as disseminated infection and encephalitis, although rare, have been documented in immunocompromised individuals (9, 10, 11, 12). Given the risk for live-attenuated vaccines to replicate and cause disease in immunosuppressed individuals, measles-containing vaccine is contraindicated in severely immunocompromised patients, including patients receiving immunosuppressive therapies such as chemotherapy, biologic response modifier, and high-dose steroid courses longer than 14 days, as well as those with uncertain immune status, with careful risk assessment prior to considering live immunizations in those who are less severely immunocompromised (6).

The differentiation between vaccine-associated measles and wild-type infection is important when considering transmission risk and determining public health and hospital exposure management. Genotype of the vaccine strain is distinct from the wild virus strain; in Canada, the NML performs PCR testing specific for genotype A, which is exclusively associated with measles immunization (5,13). Given the similar clinical presentation with fever and exanthem, timely measles virus genotyping in PCR-positive specimens can be extremely valuable in aiding public health risk assessments and exposure management. Although not available at the time of this case, Public Health Ontario now routinely tests all positive measles PCR specimens with an in-house measles vaccine genotype PCR test to rapidly identify the vaccine strain to aid in public health management decisions; all positive specimens continue to be referred to the NML for full genotyping (14).

The question arises as to whether vaccine-associated measles virus might be transmissible in immunocompromised hosts, who may have higher viral loads and be in contact with other immunocompromised children. A case of vaccine-associated measles virus in a 22-year-old immunosuppressed man who received measles-mumps-rubella (MMR) vaccination day +1,408 post-allogeneic hematopoietic cell transplantation for pre-B cell ALL, and 73 days after discontinuing immunosuppressive medications, did not report any secondary cases, despite exposure to other immunosuppressed patients at an oncology clinic while symptomatic with a rash (15). A paediatric case of vaccine-associated measles virus in a 5-year-old immunosuppressed boy 3 years post-hematopoietic stem cell transplant yielded similar outcomes, with no confirmed secondary cases (2). In this case, a cautious approach was taken despite the low risk of secondary cases, consisting of notifying all contacts, isolating susceptible immunocompromised individuals, and considering immune globulin administration (2). A 2016 systematic review found no evidence of human-to-human transmission of vaccine-associated measles virus, including among immunocompromised individuals (7).

This contrasts with the documented transmission potential of other live-attenuated vaccines. In the case of varicella-zoster vaccine, transmission risk is greatest among immunized immunocompromised patients, only occurs with rash development post-immunization, and is directly correlated with the number of skin lesions present (16).

There have been cases of vaccine-associated measles reported in immunocompetent paediatric patients, including a 2-year-old Canadian patient who developed prodromal measles symptoms 37 days after receiving their first measles-containing vaccine. After detection of measles virus in a nasopharyngeal swab by PCR, and positive measles serology, the patient was confirmed to have vaccine-associated measles by genotyping (17).

The approach to contact and exposure management of vaccine-associated measles varies in the literature and in relation to the risk or probability of wild-type measles despite recency of vaccination. In British Columbia, in the midst of a measles outbreak, a case with symptom onset 37 days post-MMR vaccination was managed as presumptive wild-type measles infection while genotyping results were pending. Public health follow-up of this case resulted in the identification of 87 contacts and administration of post-exposure prophylaxis to 45 of them before vaccine genotype was confirmed (17). In the case of a 40-year-old woman with vaccine-associated measles virus confirmed by in-house genotyping within 24 hours, post-exposure prophylaxis was not given to her 2-month-old daughter, who did not develop measles-like illness (18). Both cases occurred in immunocompetent individuals.

Our case highlights the lack of documented transmission of vaccine-associated measles virus and adds to the scant body of literature on lack of transmissibility in immunocompromised hosts. This is especially relevant as more permissive live-attenuated vaccination protocols, including those for measles-containing vaccines, develop among the growing immunocompromised population (6).

Funding Statement

No funding was received for this work.

Contributors:

Resources, D Petel, N Juma, C-L Coghill, S Wilson, A Zygmunt, M Tadros, A Campigotto, M Science; Writing – Original Draft, D Petel; Writing – Review & Editing, D Petel, D Petel, N Juma, C-L Coghill, S Wilson, A Zygmunt, M Tadros, A Campigotto, C Beck, K Kazmi, M Ali, M Science; Supervision, M Science.

Ethics Approval:

N/A

Informed Consent:

The authors confirm that patient consent has been secured from all patients.

Registry and the Registration No. of the Study/Trial:

N/A

Funding:

No funding was received for this work.

Disclosures:

The authors have nothing to disclose.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A