Original Article
Brief Report
Vaccine-Derived Poliomyelitis 12 Years after Infection in Minnesota
N Engl J Med 2011; 364:2316-2323June 16, 2011
- Abstract
A 44-year-old woman with long-standing common variable immunodeficiency who was receiving intravenous immune globulin suddenly had paralysis of all four limbs and the respiratory muscles, resulting in death. Type 2 vaccine-derived poliovirus was isolated from stool. The viral capsid protein VP1 region had diverged from the vaccine strain at 12.3% of nucleotide positions, and the two attenuating substitutions had reverted to the wild-type sequence. Infection probably occurred 11.9 years earlier (95% confidence interval [CI], 10.9 to 13.2), when her child received the oral poliovirus vaccine. No secondary cases were identified among close contacts or 2038 screened health care workers. Patients with common variable immunodeficiency can be chronically infected with poliovirus, and poliomyelitis can develop despite treatment with intravenous immune globulin.
Media in This Article
Figure 1
Administration Schedule for Intravenous Immune Globulin (IVIG) Products and Concurrent IgG Levels in the Patient.Figure 2
Magnetic Resonance Images of the Spinal Cord.Article Activity
- Article
Poliomyelitis occurs when one of three poliovirus types infects the anterior horn cells of the spinal cord and can result in flaccid paralysis, respiratory failure, and death. Among patients with poliomyelitis, poliovirus can be recovered from the stool, throat, or in rare cases cerebrospinal fluid, but excretion may be intermittent. Serologic test results may support the diagnosis but often do not confirm infection.
The worldwide eradication of polio became possible with the introduction of the inactivated poliovirus vaccine in 1955 and the oral poliovirus vaccine 6 years later. Currently, endemic infections with wild-type poliovirus are limited to areas within four countries where transmission has not been interrupted (Nigeria, Afghanistan, Pakistan, and India) and to several other countries after the importation of wild-type poliovirus.1 The number of reported cases of wild-type poliovirus infection dropped from 350,000 in 1988 to 1596 in 2009 (with the apparent elimination of poliovirus type 2 in 1999).2,3
The oral poliovirus vaccine induces humoral and mucosal immunity, is easy to administer, is more suitable than inactivated poliovirus vaccine for mass vaccination campaigns, and costs less than the inactivated vaccine.4 It also has the benefit of causing secondary infections among nonvaccinated contacts, leading to further communal immunity. However, the oral vaccine carries the risk of one case of vaccine-associated paralytic poliomyelitis for every 300,000 to 500,000 doses administered. Vaccine-associated paralytic poliomyelitis can occur either when mutations in the vaccine strain result in the return of neurovirulence or when infection occurs in a person with a B-cell immunodeficiency.4 Given the decreasing risk of wild-type poliovirus infection and the continued occurrence of vaccine-associated paralytic poliomyelitis, the inactivated vaccine has been used exclusively in the United States since 2000.5
Poliovirus strains associated with paralysis can be divided genotypically into three groups on the basis of the percent nucleotide difference from the oral poliovirus vaccine in the VP1 capsid region: the oral vaccine–like strains differ by less than 1%, the vaccine-derived poliovirus (VDPV) strains differ by 1 to 15%, and the wild-type poliovirus strains differ by more than 15%. VDPV cases can be further characterized on the basis of epidemiologic factors: strains associated with immunocompromise (iVDPV), strains associated with person-to-person or community transmission (cVDPV), and “ambiguous” strains, for which the epidemiology is unknown (aVDPV).
In March 2009, the Minnesota Department of Health investigated a case of acute flaccid paralysis associated with a positive stool culture for enterovirus.
Case Report
In December 2008, cough, purulent rhinorrhea, mild dyspnea, malaise, and a “low-grade fever” developed in a 44-year-old woman with long-standing common variable immunodeficiency; the symptoms, which she assumed were an exacerbation of her chronic sinusitis, resolved after 4 days. Two days later, cramping developed in her left calf and progressed over a period of 5 days to leg weakness, which was associated with a fall and ankle sprain, and the patient was hospitalized. On examination, she was afebrile and her cranial nerves were normal, without meningismus. Upper-extremity muscle strength was normal, and reflexes were “quite brisk.” Measurements of lower-extremity muscle strength on the right and left sides, respectively, were as follows: iliopsoas, 3/5 and 1/5; quadriceps, 3/5 and 1/5; dorsiflexors, 2/5 and 1/5; and plantar flexors, 4/5 and 3/5. A trace right-ankle jerk was noted, but all other lower-extremity stretch reflexes were absent. The plantar (Babinski) reflex was downward bilaterally. Sensory responses to a light touch, temperature changes, and pinprick were intact, with severe pain noted in both legs.
Common variable immunodeficiency was diagnosed in 1991, with subsequent diagnoses of chronic lymphoid interstitial pneumonitis (on lung biopsy), liver cirrhosis with esophageal varices of grade 1 to 2, and spruelike enteropathy (on intestinal biopsy) with chronic diarrhea (which had worsened during the 2 months before the patient's hospitalization in 2008). She had undergone splenectomy in 2006 owing to portal hypertension. B cells were absent on flow cytometry, expression of Bruton's tyrosine kinase was normal, and she was heterozygous for an R202H mutation in the transmembrane activator and calcium-modulator and cyclophilin-ligand–interactor (TACI) protein. Frequent episodes of otitis media and sinusitis were treated with antibiotics. She was being treated with prednisone, 20 mg daily, and two different brands of intravenous immune globulin every 3 weeks, with multiple changes in the dose, before the onset of her neurologic symptoms (Figure 1Figure 1
Administration Schedule for Intravenous Immune Globulin (IVIG) Products and Concurrent IgG Levels in the Patient.). The only travel of possible relevance was to southern Florida with her family 2 months earlier.By hospital day 2, the weakness had progressed to involve both upper extremities. The patient became constipated and remained afebrile. The cerebrospinal fluid contained 6 white cells per cubic millimeter (51% lymphocytes), and glucose and protein levels were normal (Table 1Table 1
Results of Laboratory Tests for Each Period during the Patient's Hospitalization.). Initial magnetic resonance imaging showed increased T2-weighted signal in the spinal-column parenchyma from T7 to the conus medullaris, without contrast enhancement. When imaging was repeated on hospital day 6, new areas of hyperintensity were noted in C3 through C7, findings that were consistent with anterior horn-cell disease (Figure 2Figure 2Magnetic Resonance Images of the Spinal Cord.).The patient's upper-extremity muscle weakness progressed (biceps strength, 3/5 on the right side and 2/5 on the left), and she continued to have severe muscular limb pain. Electromyography and nerve-conduction testing on hospital day 8 were consistent with acute motor axonal neuropathy or motor neuronopathy (anterior horn-cell disease). On hospital days 8 through 38, negative inspiratory force was reduced, and pulmonary infiltrates required noninvasive, bilevel positive airway pressure and intermittent endotracheal intubation. On hospital days 61 through 73, liver dysfunction worsened, and pneumonia and respiratory failure ensued. These problems continued, and given the multiple coexisting illnesses and persistent neurologic deficits, the family chose to withdraw support on hospital day 92, and the patient died. No autopsy was performed. Although the initial viral cultures were negative, a stool sample obtained on hospital day 74 was found to contain enterovirus and was sent to the Minnesota Department of Health for assessment of speciation.
Investigations of reportable diseases, including polio, under Minnesota state statute are classified as public health response, nonresearch by the Minnesota Department of Health Institutional Review Board.
Methods
The enterovirus isolate grew in rhesus monkey kidney cells; patterns of neutralization were identified with Lim Benyesh–Melnick antiserum pools and confirmed by neutralization with P2-specific antiserum.6 Complete genomic sequencing was performed as previously described.7,8 The complete capsid sequences of the Sabin 2 vaccine strain and 10 previously characterized cVDPV, iVDPV, and aVDPV isolates were included in comparisons of nucleotide and amino acid sequences.4,8-12 The date of exposure to the oral poliovirus vaccine that led to the patient's infection was estimated on the basis of the reported mutation rate in the capsid VP1 region (1.03% per year [95% CI, 0.93 to 1.13]).13
Household members and hospital contacts were screened to identify those with immunodeficiencies or those not vaccinated who may have been exposed to the patient's body fluids. Health care workers who performed direct patient care and groups of workers who may have had contact with the patient or her body fluids were identified.
Three weeks after the identification of the enterovirus, direct contact with each potentially exposed health care worker from the two facilities where she was hospitalized was made by each institution's occupational health department by means of the department's standard communication method. Four questions were asked: “To the best of your knowledge, have you ever received polio vaccine?”; “Have you been told that you have any of the conditions such as the ones listed here: B-cell deficiency, splenectomy, chronic lymphocytic leukemia, human immunodeficiency virus infection, bone marrow transplant, antibody deficiency, or combined immunodeficiency?”; “In the past 5 months have you received any of the following treatments or medications including rituximab (Rituxan, MabThera), chemotherapy, or a drug to prevent transplant rejection?”; and “In the past 5 months have you experienced either new onset of severe muscle weakness OR new onset of severe muscle cramping?” Health care workers were asked to call the Minnesota Department of Health if they answered “no” to the first question and “yes” to the next three questions, or if their answer to any of the four screening questions was “I don't know.” In-depth interviews were conducted with respondents to further clarify their potential risk of poliovirus infection. In addition, the medical records of three hospital roommates of the patient were reviewed, and their primary care physicians were contacted.
Results
The enterovirus isolate was neutralized by poliovirus type 2 antiserum. Sequencing of the capsid VP1 region identified poliovirus type 2 and was divergent by 12.3% from previously published nucleotide sequences of the Sabin 2 oral poliovirus vaccine; the complete capsid region was 11.7% divergent, and the 5' untranslated region (5' UTR) and complete capsid region combined was 11.0% divergent. The patient's isolate was most similar to other known iVDPV strains when compared with neutralizing antigenic amino acid substitutions (Figure 3Figure 3
Sequences within or near the Neutralizing Antigenic (NAg) Sites for the Patient's Isolate.). The exposure to oral poliovirus vaccine that led to the patient's infection was estimated to have occurred 11.9 years earlier (95% CI, 10.9 to 13.2). Nucleotide substitutions were identified at Sabin 2 vaccine attenuation sites (nucleotide 481 in the 5' UTR and amino acid 143 VP1 [in the latter case, isoleucine to threonine]).14,15 The patient's household included her husband and two children, 6 and 13 years of age (born in 2002 and 1995, respectively). No neurologic symptoms were reported by the patient's immediate family members. The patient and her husband reportedly had received all recommended childhood vaccinations. One child received the primary series of oral poliovirus vaccine at 13.0, 12.8, and 12.6 years before the patient's isolate was collected; the second child received only the inactivated poliovirus vaccine.
A total of 2038 health care workers were screened for a history of immunodeficiency, polio vaccination, and neurologic symptoms; 13 of the workers contacted the Minnesota Department of Health. None were found to be at risk (i.e., unvaccinated or immunocompromised) or to have had a neurologic illness consistent with polio after the secondary interview, and the same was true for the patients who shared a hospital room with the patient.
Discussion
This patient had the first nonimported case of paralytic poliomyelitis and the second case of VDPV infection reported in the United States since the discontinuation in 2000 of oral poliovirus vaccinations.6 Coincidentally, the previous case of VDPV infection, in 2005 (involving poliovirus type 1), occurred in the same hospital, which increased the level of suspicion for this infection. Multiple stool cultures for virus early in the hospitalization failed to identify the poliovirus, indicating that repeated testing may be necessary in some patients. This isolate was consistent with other highly divergent, neurovirulent iVDPVs. Substitutions at nucleotide 481 in the 5' UTR and amino acid 143 of VP1 are known to be the principal determinants of attenuation for the Sabin 2 vaccine strain,14,15 and mutations like those observed in the isolate in this case are associated with reversion to neurovirulence.
Typically, in immunocompetent persons who have been vaccinated, the oral poliovirus is cleared within 6 weeks after vaccination and the wild-type poliovirus is cleared within 8 weeks.16 Among persons with B-cell immunodeficiency, poliovirus replication can continue for much longer periods. It is known that poliovirus evolves at a constant rate, about 1% per year, suggesting that infection in this patient occurred between 11 and 13 years earlier, a time frame that is consistent with the date when a household member was given the oral vaccine.13 Although 23 iVDPV cases have been reported, only 1 case has involved a longer estimated time from exposure to the latest documented shedding (>19 years, as of 2005) in a patient without paralysis.4,17
This case is characterized by the longest incubation period associated with the oral poliovirus vaccine that eventually resulted in poliomyelitis as described. No clear treatment or public health approach has been established for persons with long-term shedding of poliovirus who have received the oral vaccine. Without known effective treatments to eliminate shedding, paralytic disease can occur among patients with B-cell immunodeficiency after more than a decade of undetected poliovirus replication since the initial infection, as highlighted in this case.
In this patient, the intravenous administration of immune globulin did not prevent the acquisition of infection, stop the long-term poliovirus infection, or prevent the development of paralytic poliomyelitis. One possible explanation for this patient's disease is that there may have been lower titers of antibody against poliovirus type 2 in the immune globulin preparations the patient had recently received. The preparation was changed about 60 days before the onset of symptoms. An attempt to identify antipoliovirus antibody levels in the lots of immune globulin received before the onset of her symptoms was unsuccessful. A clear link between treatment changes and disease onset is unlikely, given the length of infection and the multiple changes in the dosage and brand of immune globulin. Although variation in certain antibodies can occur among manufacturers and lots, there are no data available to suggest that differences in the antibody titer of the product are associated with the risk of poliomyelitis.
Since oral poliovirus vaccinations were discontinued in the United States and other countries, fewer persons have the potential immunologic boosting that results from secondary exposure to the oral poliovirus vaccine. This may result in a more rapid age-dependent drop in antipoliovirus antibody levels among plasma donors, and therefore decreased protection among B-cell–deficient patients who receive intravenous immune globulin. Producers of intravenous immune globulin are required to maintain minimum titers of antibodies to any one of the three poliovirus types, but the minimum titer that provides protection against poliomyelitis among chronically infected persons with B-cell immunodeficiencies is unknown.18 Despite having a total IgG level above 600 mg per deciliter when symptoms developed, this patient was not adequately protected by the supplemental immune globulin she received. It is also not known what other factors, unrelated to the intravenous immune globulin, may put chronic VDPV carriers at risk for progression to disease.
The risk of vaccine-associated paralytic poliomyelitis in persons with primary B-cell immunodeficiency is estimated to be increased by a factor of 3000 after exposure to the oral poliovirus vaccine.19-21 The oral vaccine is contraindicated in persons with immunodeficiency and in their household members. In addition, patients with B-cell immunodeficiency who were exposed to the oral poliovirus vaccine before 2000 may still be at risk for virus shedding and poliomyelitis.
VDPV cases represent an additional challenge to the eradication of polio. Persons with chronic VDPV infection represent a potential persistent reservoir that could lead to the reintroduction of poliovirus. With polio eradication on the horizon, this case highlights the need for continued surveillance for VDPV and cases of acute flaccid paralysis even in countries that use the inactivated polio vaccine, particularly in patients with primary B-cell immunodeficiency.12 It also underscores the need to develop effective antiviral therapy for patients with chronic poliovirus infections.22 Finally, the establishment and maintenance of high vaccine coverage (either with the oral or the inactivated poliovirus vaccine) is required to prevent the spread of VDPV until the prevention, detection, and treatment of poliovirus infections can be ensured. These steps will assist in securing the next great public health success.
Supported in part by a grant (3U01CI000313) from the Emerging Infections Program, Centers for Disease Control and Prevention.
The findings and conclusions reported here are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the following persons for their efforts during this project: Richard Danila, Kristen Ehresmann, Sara Lowther, Claudia Miller, and Elly Pretzel at the Minnesota Department of Health; Gregory Armstrong, Jane Iber, Olen Kew, Eric Mast, Steven Oberste, Mark Pallansch, and Jane Seward at the Centers for Disease Control and Prevention; Vicki Carlson, Karen Ferrara, Gary Kravitz, and Doris Nordbye at the United Hospital and Clinic; Anita Guelcher, Chris Hendrickson, and Lisa Ide at the University of Minnesota Medical Center, Fairview; and John Modlin at the Dartmouth–Hitchcock Medical Center.
Source Information
From the Minnesota Department of Health, St. Paul (A.S.D., J.H., A.M., C.L., L.B., J.C., E.C., S.F., R.L.); the University of Minnesota, Minneapolis (S.K.); and the Centers for Disease Control and Prevention, Atlanta (G.S.W., J.H.S., C.C.B.).
Address reprint requests to Dr. DeVries at the Minnesota Department of Health, P.O. Box 64975, St. Paul, MN 55164, or at aaron.devries@state.mn.us.
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- Citing Articles (3)
Citing Articles
1
Olen Kew. (2012) Reaching the last one per cent: progress and challenges in global polio eradication. Current Opinion in Virology 2:2, 188-198
CrossRef2
P. D. Minor. (2011) The Polio-Eradication programme and issues of the end game. Journal of General Virology
CrossRef3
(2011) Vaccine-Derived Poliomyelitis 12 Years after Infection. New England Journal of Medicine 365:14, 1355-1355
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