Prolonged Poliovirus Excretion in an Immunodeficient Person with Vaccine-Associated Paralytic Poliomyelitis

Recently completed molecular studies of poliovirus isolates suggest that viral replication of vaccine-related polioviruses may have persisted for as long as 7 years in a patient with vaccine-associated paralytic poliomyelitis (VAPP) in whom common variable immunodeficiency syndrome (CVID) previously had been diagnosed. This report summarizes the clinical and virologic data and discusses the possible implications of these new findings for the global polio eradication initiative, which include how and when to discontinue vaccination when polio has been eradicated.

The case-patient, a man born in 1964, had a history of multiple episodes of upper respiratory infections, otitis media, recurrent fever, chronic cough, sinusitis, and skin infections. At age 9 years, he was diagnosed with allergies to dogs, cats, food items, grass, and trees. At age 12 years, he was hospitalized because of lung infiltrates and maxillary sinusitis; CVID syndrome was diagnosed based on quantitative immune globulins of 42 mg/dL for IgG (normal: 639-1349 mg/dL), 3.8 mg/dL for IgA (normal: 70-132 mg/dL), and 4.5 mg/dL for IgM (normal: 56-352 mg/dL). He was placed on monthly therapy with fresh frozen plasma and maintained IgG levels of 62-330 mg/dL during 1975-1981. His vaccination history included three doses of inactivated poliovirus vaccine administered during 1964-1965 and four doses of trivalent oral poliovirus vaccine (OPV) administered during 1967-1974.

In July 1981, at age 16 years, he had fever (104 F {40 C}) and generalized weakness following an episode of diarrheal illness. Four days after onset of fever, he had onset of a stiff neck, diplopia, and generalized paralysis and required mechanical ventilation. Paralytic poliomyelitis was diagnosed. The clinical course included multiple hospital admissions for pneumonia and urinary tract infections. He was ventilator-dependent from 1981 until his death in October 1990.

Stool specimens were obtained from the patient at 11, 23, 48, 126, 159, and 200 days after onset of paralysis in July 1981. Poliovirus type 1 was isolated from each specimen. Initial characterization of isolates by RNase T1 oligonucleotide fingerprinting was inconclusive. Nucleotide sequences encoding the major capsid protein VP1 were determined for each isolate. The first (day 11) isolate contained two subpopulations, equally divergent from the Sabin 1 vaccine strain (by 10% of VP1 nucleotides), and differing from each other by 6% of VP1 nucleotides. In contrast, each subpopulation differed from wild type 1 poliovirus isolates by 19%-24% of VP1 nucleotides. Polioviruses isolated from specimens obtained after day 11 were derived from only one subpopulation. VP1 sequences of these isolates revealed a stepwise divergence from the Sabin 1 sequence at a rate of about 1.1% per year. By assuming that the rate of sequence evolution was constant throughout the infection, the initial infection was estimated to have occurred at approximately the time of receipt of the last OPV dose in 1974.

Reported by: Respiratory and Enteric Viruses Br, Div of Viral and Rickettsial Diseases, National Center for Infectious Diseases; Child Vaccine Preventable Disease Br, Epidemiology and Surveillance Div, and Polio Eradication Activity, National Immunization Program, CDC.

Editorial Note

Editorial Note: Although the replication of poliovirus in immunocompetent persons is of limited duration (ranging from several days to 3 months) (1), poliovirus may replicate in immunodeficient persons for considerably longer periods (2). For example, vaccine-related poliovirus has been recovered from cerebrospinal fluid of a patient 1 year after vaccination and continually from stools of two patients for durations of 21 months and 31 months, respectively, after vaccination (3). In a patient with agammaglobulinemia, replication of vaccine virus persisted for at least 684 days (4).

The case described in this report is exceptional because it is the only known VAPP case in an immunodeficient person in which immunodeficiency had been diagnosed before onset of paralytic manifestations (5). In all other cases of VAPP among immunodeficient persons, the paralytic manifestations were the event that prompted consideration of the diagnosis of immunodeficiency. There is no evidence that this virus strain caused other cases of VAPP.

Because stool specimens were obtained only after onset of paralysis, the date the patient initially was infected with the vaccine-derived polioviruses cannot be determined. The extensive sequence differences of the isolates from the parental Sabin 1 strain suggest prolonged replication of the virus in one or more persons since administration of the original OPV dose. Because the two virus subpopulations infecting the patient were equally divergent from the Sabin 1 strain, it is likely that these viruses were derived from a single initiating OPV dose. Divergence of the two subpopulations occurred an estimated 2.5 years before onset of paralysis. The time of the initial infection estimated from VP1 evolution rate data is approximately when the patient received his last dose of OPV. Although the time for following the sequence evolution of the vaccine-derived virus was short (189 days), the rate of genomic evolution is similar to the rate determined for wild type 1 polioviruses circulating during a 10-year period (6). The apparent similarity in the rates of evolution of virus nucleotide sequences during replication in immunodeficient and normal persons is not unexpected, because under both conditions most (greater than 90%) of the observed mutations do not alter virus proteins and would not be subject to immune selection. However, interpretation of the virologic data presented in this report is limited by the inability to directly determine the time of the initial infection and by the assumption that the rate of VP1 sequence evolution in immunodeficient persons is constant over several years.

The case described in this report was reviewed by an external group of experts convened by CDC in Atlanta on April 2, 1997, and during the meeting of the World Health Organization (WHO) Technical Consultative Group (TCG) on the Global Eradication of Poliomyelitis in Geneva, Switzerland, on April 28, 1997 (7). The conclusion that chronic poliovirus infection of immunodeficient persons is uncommon is based on the absence of any other reported case with a similar course during approximately 30 years of polio surveillance in the United States, including 32 cases of paralytic polio in immunocompromised persons studied since 1980 (8,9). However, both groups reaffirmed the need for specific research to determine 1) the extent of vaccine virus circulation in countries that rely solely on mass vaccination campaigns to deliver OPV and 2) the frequency and duration of vaccine virus shedding in immunocompromised persons, including persons infected with human immunodeficiency virus.

Based on an overall review of available data, the TCG concluded that the evidence is consistent with plans to discontinue polio vaccination after wild poliovirus has been eradicated. However, TCG also recommended that additional scientific studies should be conducted to assure that vaccine viruses will not continue to circulate and cause disease after vaccination has been stopped. A detailed strategy for discontinuing vaccination must be clearly defined to achieve the full benefits of polio eradication (10). WHO is sponsoring studies to determine how and when vaccination can be terminated.

References

1. Gelfand HM, LeBlanc DR, Fox JP, Conwell DP. Studies on the development of natural immunity to poliomyelitis in Louisiana -- II: description and analysis of episodes of infection observed in study households. Am J Hyg 1957;65:367-85.

2. Dowdle WR, Birmingham ME. The biologic principles of poliovirus eradication. J Infect Dis 1997;175:S286-S292.

3. Working Party on Hypogammaglobulinemia. Hypogammaglobulinemia in the United Kingdom. Medical Research Council Special Report Series 1971;310:1-319.

4. Hara M, Saito Y, Komatsu T, et al. Antigenic analysis of polioviruses isolated from a child with agammaglobulinemia and paralytic poliomyelitis after Sabin vaccine administration. Microbiol Immunol 1981;25:905-13.

5. Sutter RW, Prevots DR. Vaccine-associated paralytic poliomyelitis among immunodeficient persons. Infect Med 1994;11:426,429-30,435-8.

6. Kew OM, Mulders MN, Lipskaya GY, da Silva EE, Pallansch MA. Molecular epidemiology of polioviruses. Semin Virol 1995;6:401-14.

7. Cochi SL, Sutter RW, Kew OM, Pallansch MA, Dowdle WR. A decision tree for stopping polio immunization: technical consultation on the global eradication of poliomyelitis, Geneva, Switzerland, April 28, 1997. Geneva, Switzerland: World Health Organization, 1997; document no. EPI/POLIO/TECH.97/WP18.

8. CDC. Paralytic poliomyelitis -- United States, 1980-1994. MMWR 1997;46:79-83.

9. Strebel PM, Sutter RW, Cochi SL, et al. Epidemiology of poliomyelitis in the United States: one decade after the last reported case of indigenous wild virus-associated disease. Clin Infect Dis 1992;14:568-79.

10. World Health Organization. Report of the technical consultation on global eradication of poliomyelitis, April 28, 1997: conclusions and recommendations. Geneva, Switzerland: World Health Organization, 1997; publication no. TCG_REC_97.Doc.

    
    

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