Clinical manifestations

Presentation and course

More than 90% of poliovirus infections are asymptomatic. Approximately 4% to 8% of infected patients develop symptoms of acute poliomyelitis, which can be separated into two distinct clinical phases: the “minor illness,” with an incubation period of 3 to 7 days, and the “major illness,” with onset of symptoms generally 9 to 12 days after exposure (84). During the minor illness, patients present with constitutional symptoms (eg, fever, headache, nausea and vomiting, coryza, and sore throat), which are typically self-limiting, lasting 1 to 2 days. Major illness is associated with CNS infection, which has been estimated to occur in 0.1% to 1.0% of all poliovirus infections (131; 145).

During the major illness, patients may demonstrate signs of meningeal irritation, asymmetric flaccid weakness, muscle spasms, normal or accentuated muscle stretch reflexes, and hyperesthesias with preserved somatosensation. The major illness includes all forms of CNS disease caused by poliovirus, including aseptic meningitis, polioencephalitis, bulbar polio, and paralytic poliomyelitis. These manifestations may occur alone or in combination. About one third of young children who develop the major illness experience a biphasic illness with symptoms of the minor illness preceding onset of CNS disease (82; 195). The major illness often begins with aseptic meningitis. One third of cases are limited to meningitis without detectable motor neuron impairment, which resolves within 5 to 10 days. Polioencephalitis can occur as well, manifesting as obtundation or agitation, autonomic dysfunction and upper motor neuron signs of spasticity, increased deep tendon reflexes, and Babinski signs. Muscle pains, muscle cramps, fasciculations, and radicular pain rarely occur without paralysis, which they precede by 24 to 48 hours.

Paralytic poliomyelitis accounts for only 0.1% to 2.0% of all poliovirus infections and can be divided into three types: spinal, bulbar, and bulbospinal (131; 83; 136). Muscle weakness is preceded by intense myalgias of the involved limbs and the axial skeleton, and it may be relieved by exercise. The hallmark of paralytic poliomyelitis is asymmetric motor paresis, which ranges from mild weakness of a single extremity to complete quadriplegia and respiratory muscle paralysis.

Proximal limb muscles are more involved than distal, and legs are more commonly involved than arms. The reflexes are initially brisk and then become absent over time. The pace of development of the paresis ranges from several hours to several days. Rarely, transverse myelitis with paraparesis, urinary retention, sensory complaints and signs, and autonomic dysfunction may be seen (155; 67). Bulbar poliomyelitis occurs in 5% to 35% of paralytic cases and most commonly affects the ninth and tenth cranial nerves.

Some affected patients develop profound leg weakness that produces severe secondary orthopedic problems, limb deformities, and contractures. Common resulting neuro-orthopedic deformities are pes equinovarus and paralytic pes cavus.

Acquired quadrupedal human gait. In the past, poliomyelitis was the most common cause of an acquired quadrupedal human gait (as distinct from normal developmental or volitional quadrupedal gaits) (109). The most dramatic example was the boy photographed by English American photographer Eadweard Muybridge (1830-1904) and American neurologist Francis Xavier Dercum (1856-1931) in 1885.

In a large series of patients hospitalized with poliomyelitis, 3 of 98 patients (3%) with disturbances of locomotion were noted to be “hand walkers” (among a total of 108 for whom function was recorded) (79). Early 20th-century cases of acquired quadrupedal gaits following poliomyelitis, with photographic documentation of a quadrupedal stance were reported, for example, by Austrian pediatrician and neurologist Julius Zappert (1867-1942), Austrian orthopedist Hans Spitzy (1872-1956), German orthopedic surgeon Oskar Vulpius (1867-1936), and German Swiss neurologist Robert Paul Bing (1878-1956) (203; 148; 180; 90; 25; 109).

Vulpius’s case (as illustrated by German physician J Ibrahim in a textbook chapter titled “The organic nervous diseases of childhood”) used hands-and-knees crawling, whereas the cases of Bing and Zappert used hand-and-feet crawling. More recent examples of quadrupedal gaits in adults who survived poliomyelitis as children were identified in various countries during the latter half of the 20th century, most often in Africa and Asia (109).

Chronic poliomyelitis infections have occurred infrequently in children with immunodeficiencies who have received the live oral vaccine (164; 202; 200). Onset usually occurs several months after vaccination, and patients may present with a lower motor neuron paralysis or progressive cerebral dysfunction.

Post-polio syndrome. As many as 20% to 30% of patients who recover from paralytic poliomyelitis experience new onset of slowly progressive muscle weakness, pain, atrophy, and fatigue many years after the acute illness, most commonly 3 to 4 decades after acute illness (97; 114; 115; 45). This is known as post-polio syndrome. Both muscle and joint pain are frequent. Patients with a history of bulbar poliomyelitis are particularly at risk of developing dysphagia as well as sleep-disordered breathing abnormalities.

In a retrospective study of 400 patients with poliomyelitis attending a specialized outpatient clinic in Barcelona, Spain, post-polio syndrome was more frequent in women (58%) (171). The mean age at symptom onset was 52 years, and was earlier in women. Common problems included pain (85%), loss of strength (40%), fatigue (66%), cold intolerance (20%), dysphagia (12%), depressive symptoms (32%), and cognitive complaints (9%). Fatigue or tiredness, depression, and cognitive complaints were significantly more frequent in women. Electromyographic findings suggestive of post-polio syndrome were reported in 59%.

Prognosis and complications

Morbidity and mortality in poliomyelitis vary depending on the severity of illness. Although a minor illness typically causes little or no sequelae, major illness can lead to muscle paralysis, respiratory arrest, and death. Case fatality is 1.5% to 6.7%, assuming availability of optimal care (56). A study on a particularly virulent outbreak of wild poliovirus in the Republic of Congo found up to 92% of cases had residual paralysis 60 days after disease onset (152). Efficient surveillance and proactive case management may improve morbidity and mortality. Complications of poliomyelitis include respiratory distress often necessitating mechanical ventilation, dysphagia, and pneumonia (66; 69). Prolonged immobility may lead to decubitus ulcers and limb contractures (69). Provocative paralysis (which can occur following intramuscular injection) should also be anticipated when managing poliomyelitis.

Orthopedic issues include hip, back, and extremity pain; muscle strain; ligament sprain; spondylosis; kyphoscoliosis; exaggerated lumbar lordosis; genu recurvatum; and other deformities (47; 69; 184).

In the past, poliomyelitis was probably the most common cause of an acquired quadrupedal human gait (as opposed to normal developmental or volitional quadrupedal gaits) (107; 108; 109).

Indeed, in a large series of patients hospitalized with poliomyelitis, 3 of 98 patients (3%) with disturbances of locomotion were noted to be “hand walkers” (among a total of 108 for whom function was recorded) (79). Note that the term “hand walkers” generally denoted those that walked with a quadrupedal gait but very rarely referred to individuals who learned to walk exclusively on their hands.

Postpoliomyelitis patients transitioning to adulthood have a high frequency of falls, osteoporosis, and fractures (178). Bone mineral density tends to be worse in the worst-affected leg (178). In a retrospective analysis of 204 postpoliomyelitis patients, recurrent falls were documented in 39% of patients and osteoporosis in 21%. Not surprisingly, osteoporosis was more frequent in women and patients with fractures. At least one fracture occurred in half (52%) of the patients and more than one fracture occurred in 40% of the patients. The median age for the first fracture was 58 years (range, 30 to 83 years) and most fractures occurred in the affected limb (73%).

Sleep disturbances also occur more frequently and are most commonly associated with the bulbar variant of poliomyelitis (47; 64; 12).

Physical disabilities experienced often lead to emotional symptoms (69). Psychotherapy, group rehabilitation, regular follow-ups, and patient education methods can be used to improve mental status and overall well-being (64).

Patients with post-polio syndrome develop generalized fatigue, muscle weakness, atrophy, pain, fasciculations, cramps, and cold intolerance occurring several years (usually more than 15 years) after the acute episode (77; 47; 97; 114; 115; 45).

Clinical vignette

A 10-year-old boy living in Nigeria was brought to the pediatric emergency department for evaluation of a 2-day history of malaise and diarrhea, with both an increased frequency of stooling and the passage of watery, non-bloody stools. On examination, he was febrile with a temperature of 38.5 degrees Celsius. His abdomen was non-tender, and he had no palpable organomegaly. On neurologic examination, he was conscious and fully oriented but lethargic with mild neck stiffness. He had no cranial nerve palsy. Muscle tone was mildly reduced in the right leg compared to the left. Power was grade 4/5 on the Medical Research Council scale in the right ankle and 5/5 in all other muscle groups. Deep tendon reflexes were grade 1 at the right ankle and grade 2 at the other sites. Plantar response was flexor bilaterally. Sensory examination was unremarkable. Complete blood count, erythrocyte sedimentation rate, electrolytes, and stool (for microscopy, culture, and sensitivity) were ordered.

The following day, his motor strength was reduced to 3/5 in the right leg, and within 48 hours, it was 1/5 and 4/5 on the right and left legs, respectively. Blood count was unremarkable. CSF analysis revealed a mild increase in leukocytes (18 cells/µl) and protein (45 mg/dl). CSF glucose was normal (70 mg/dl). Stool was negative for pathogenic bacteria or blood. Stool samples were positive for wild-type poliovirus 1. He was maintained on bed rest, and specific instruction was given to be vigilant for respiratory distress and to avoid intramuscular injections.

Further interview with the mother revealed that the boy did not complete his polio immunizations as he had only the oral polio vaccine 1 at 6 weeks after birth but did not receive the second and third oral polio vaccine doses in the subsequent months. She could not remember if he had any booster doses at 18 months or later. Three weeks later, power was 2/5 on the right and 4/5 on the left legs.

Biological basis

Etiology and pathogenesis

Poliomyelitis is an infection caused by the polioviruses, which are human enteroviruses. Three poliovirus serotypes are distinguished from one another by type-specific antisera (10). Before the introduction of poliovirus vaccines, naturally occurring polioviruses circulated in temperate climates with a marked seasonal variation resulting in peak activity between July and October and low levels between December and May. Poliovirus type 1 was responsible for 80% to 90% of all epidemics of paralytic poliomyelitis in the United States (22; 145).

Poliovirus is a nearly spherical icosahedral-shaped virus, as revealed by x-ray crystallography and electron microscopy.

The poliovirus genome consists of a single-stranded, positive-sense polarity RNA molecule, which encodes a single polyprotein (53).

The 5' non-translated region (NTR) harbors two functional domains, the cloverleaf and the internal ribosome entry site (IRES). The 5' NTR is covalently linked to the viral protein VPg.

The cellular life cycle of poliovirus is somewhat complicated (34; 53).

First, poliovirus binds to the cell surface macromolecule CD155, which functions as the virus receptor (53). Viral RNA uncoating is mediated by receptor-dependent conformational changes and destabilization of the virus capsid (34; 53).

The particles are then internalized by an actin- and tyrosine kinase-dependent, but clathrin- and caveolin-independent, mechanism (34). The release of the viral genome takes place only after internalization from an endocytotic compartment localized within 100 to 200 nm of the plasma membrane (34). On release of the RNA genome, the empty capsid is transported away along microtubules (34). Translation of the viral RNA is mediated by internal ribosome entry site (IRES), an RNA element that allows for translation initiation in a cap-independent manner, as part of protein synthesis. Proteolytic processing of the viral polyprotein produces mature structural and nonstructural proteins. The positive-sense RNA serves as the template for complementary negative-strand synthesis. Newly synthesized positive-sense RNA molecules can either serve as templates for translation or associate with capsid precursors to undergo encapsidation, which ultimately generates progeny virions. Lysis of the infected cell results in release of infectious progeny virions.

Poliovirus, as with other enteroviruses, is commonly spread by fecal-hand-oral transmission. After ingestion, the poliovirus implants in the oropharynx and small bowel and penetrates the mucosa via specialized microfold cells and other epithelial cells overlying submucosal lymphoid tissues (83; 149; 147). After replication in the submucosal lymphatic tissue, the virus spreads to the lymph nodes, and then to the bloodstream (27). In a minority of infections, further replication of virus in reticuloendothelial tissues leads to a major viremia. CNS invasion is much more likely to occur during secondary viremia but can infrequently occur during primary viremia. As demonstrated in experimental studies in primates, tonsils, mesentery lymph nodes, and intestinal mucosa are major target sites of viral replication (177). Early in the infectious process, poliovirus replication occurs in both epithelial cells (which accounts for virus shedding in the gastrointestinal tract) and lymphoid/monocytic cells in tonsils and Peyer patches (which accounts for viremia) (177). Genetic variants in innate immune defenses and cell death pathways may contribute to the clinical presentation of poliovirus infection (11).

The exact route through which poliovirus enters the CNS is unclear (142; 143; 144; 147). There is some suggestion based on animal models that viral replication in skeletal muscles precedes transport of poliovirus to the spinal cord via the peripheral nerve (31). The anterior horn cells and other motor neurons are selectively vulnerable to poliovirus infection (28; 96; 78; 49). Mitochondria are important in poliovirus-induced apoptosis and mitochondrial dysfunction results from an imbalance between pro- and anti-apoptotic pathways (26). Pathologic changes occur within 1 to 2 days after poliovirus infects the neuron, and an inflammatory response ensues with meningeal, perivascular, and parenchymal infiltrates (30; 29; 94; 199). Neuronal destruction by lytic replication of the poliovirus causes paralytic poliomyelitis in less than 1% of those infected (147). Individuals who have had polio may experience denervation with subsequent reinnervation for many years. Many have spotty loss of anterior horn motor neurons, and the anterior horn may be shrunken and sclerotic in the chronic stage.

Although the precise cause of post-polio syndrome is unknown, the cause is probably related to overstress or exhaustion of the residual surviving motor units following acute poliovirus infection. Terminal elements of surviving alpha motor neurons that sprout to reinnervate adjacent myofibrils following initial infection are believed to become overstressed (75; 04; 150; 176). Muscle fatigue in post-polio syndrome may be due to impaired activation beyond the muscle membrane at the level of excitation-contraction coupling or may have a central origin. Other possible mechanisms have been considered, including immunologic events and other virus-host interactions (52).

Vaccine-derived polioviruses and vaccine-associated paralytic poliomyelitis. Vaccine-derived poliovirus (VDPV) results from the use of oral poliovirus vaccine in low- and middle-income countries. VDPVs are rare strains of poliovirus that have genetically mutated from the attenuated strains contained in the oral polio vaccine. Normally, when a child is vaccinated, the weakened vaccine strains replicate in the intestine and enter the bloodstream, triggering a protective immune response. Rarely, during this replication process, some vaccine virus may genetically mutate from the original attenuated strain, become neurovirulent, and cause vaccine-associated paralytic poliomyelitis. In addition, like infections with wild polioviruses, vaccinated children typically excrete the vaccine strains of poliovirus for 6 to 8 weeks. If a population is under-immunized, there may be enough susceptible children for the excreted attenuated poliovirus to begin circulating in the community; with uninterrupted recirculation, the attenuated vaccine strain may reacquire neurovirulence, at which time these are called circulating vaccine-derived polioviruses (cVDPV). Prolonged replication of VDPV has also been observed in people with immune deficiency disorders. In the absence of an adequate immune response, such individuals may excrete immunodeficiency-related VDPVs (or iVDPVs) for prolonged periods. Most patients with iVDPVs either stop excretion within 6 months or die. Finally, ambiguous VDPVs (aVDPVs) are either isolated from people with no known immunodeficiency or isolated from sewage whose ultimate source is unknown. As poliovirus serotypes are eliminated, it is necessary to continue to shift away from the use of live attenuated vaccines to minimize the risk of VDPV.

Therefore, there are three categories of VDPV:

(1) Circulating VDPVs (cVDPVs): VDPV for which there is evidence of human-to-human transmission in the community. Isolates must either be from (1) at least two individuals (not necessarily cases of acute flaccid paralysis) who are not direct contacts; (2) from one individual plus environmental samples; or (3) from at least two environmental samples collected more than 2 months apart or from more than one distinct collection site. Low levels of population immunity to polio (due to low vaccination coverage) increase the risk of cVDPV (08; 09).

(2) Immunodeficiency-associated VDPVs (iVDPVs): VDPV isolated from patients with primary immunodeficiencies. Patients with iVDPV are potential poliovirus reservoirs that can potentially reintroduce polioviruses into a community in the post-eradication era. Roughly a third of patients with iVDPVs have never had paralysis (174).

(3) Ambiguous VDPVs (aVDPVs): VDPV isolates (human or environmental) without evidence of circulation and from individuals with no known immunodeficiency. These may subsequently be reclassified as “circulating” if genetically linked isolates are identified.

Epidemiology

Accurate prevalence figures estimating the number of survivors of poliomyelitis are not available (93).

Global Polio Eradication Initiative (GPEI). The Global Polio Eradication Initiative (GPEI), launched in 1988, represents the single largest, internationally coordinated public health project to date. GPEI is a public-private partnership led by national governments with six core partners: the World Health Organization (WHO), Rotary International, the U.S. Centers for Disease Control and Prevention (CDC), the United Nations Children’s Fund (UNICEF), the Bill & Melinda Gates Foundation, and Gavi, the Vaccine Alliance. Its goal is to eradicate polio worldwide.

To understand the discussion of polio trends and current activity in different WHO regions, it is necessary to have some familiarity with how the WHO categorizes different world regions.

The complexities of war, poverty, and pandemic (COVID-19) have all complicated the efforts of GPEI and triggered debate on the economic return of polio eradication, as well as financing, feasibility, and strategy (20; 14; 16; 15; 57; 58; 163; 89; 13; 186; 185; 187). During the COVID-19 pandemic, immunization programs in many countries experienced setbacks (134; 167; 170; 55). Marked differences in the reporting of poliomyelitis cases in underdeveloped countries were initially quite large, forcing adjustments for underreporting to generate estimates of actual disease incidence (57). Economic analyses have found strong economic justification for the GPEI despite the rising costs of the initiative; the positive net benefits of the GPEI remain robust over a wide range of assumptions (57).

The "end game" will also depend on the vaccines used in different countries. The standard vaccines have been the inactivated polio vaccine (Salk) and the attenuated oral polio vaccine (Sabin). Unfortunately, the Salk vaccine is associated with various logistical problems that make it less suitable in poorly developed countries, including its minimal intestinal mucosal immunogenicity, its relatively high cost, and various operational issues (133). Although the Sabin vaccine is easier and cheaper to use, and is associated with greater primary intestinal mucosal immunogenicity, it has contributed to vaccine-associated and vaccine-derived paralytic poliomyelitis cases (133). Newer polio vaccines will obviate some of the problems of the Salk and Sabin vaccines, making them better choices to finalize disease eradication (133).

Table 1. Current Vaccines and Key Issues Relevant to the Endgame of Polio Eradication

Table 2. New Polio Vaccines in Different Stages of Development

Poliovirus transmission is primarily detected through syndromic surveillance for acute flaccid paralysis among children younger than 15 years old, with confirmation by laboratory testing of stool specimens.

Public health messaging in native languages with images of polio victims is used to increase public awareness of the problem and the availability of protective vaccines.

Polio worldwide. Polio cases have decreased by over 99% since 1988, from an estimated 270,000 to 350,000 cases in more than 125 endemic countries to 694 reported cases due to wild-type virus in 2021 (6 due to wild-type poliovirus type 1 from Afghanistan, Pakistan, and Malawi and 688 due to cVDPV, 672 due to cVDPV2, and 16 due to cVDPV1) (57; 63; 70; 128; 129; 141; 72; 86; 50; 159). Reported poliomyelitis incidence declined by roughly 2 orders of magnitude between the mid-1980s and the mid-2000s, which taking account of the adjustments needed for underreporting, is less dramatic than the nearly 3 orders-of-magnitude decrease in estimated decline in incidence (57; 50).

The result is that an estimated 2.2 million cases of paralytic polio were averted between 1988 and 2018 (57; 50). The WHO estimates are somewhat greater (133).

As more countries have progressively become polio-free, eradication efforts have been more focused on the Eastern Mediterranean WHO regions (50). Unfortunately, some areas free from wild-type poliovirus have maintained insufficient vaccine coverage to ensure that they remain polio-free.

The CDC and WHO have collected data concerning worldwide polio by country that show the progress, and the limitations of progress, in incident cases of poliomyelitis from 2012 through 2021 (139; 156; 138; 54; 99; 74; 24; 159). In that interval, Afghanistan, Pakistan, and Nigeria have contributed the most cases, with scattered additional cases, particularly in African countries (50).