Mysterious Paralysis Affecting Children: Are Vaccines to Blame?
Eli Kammerman - October 28, 2018
[Editor's comment: The two-hit hypothesis presented addresses a cellular, but not a molecular, mechanisms of pathophysiology involving vaccination concurrent with enterovirus infection. Whether molecular mimicry or other known molecular mechanisms of vaccine induced autoimmunity also play a role remains to be tested.]
A mysterious disease is paralyzing kids in 22 states. A three-year-old who could barely hold up his own head was featured on the news after contracting a polio-like illness that started with a runny nose and turned into something much more serious. Doctors diagnosed him with Acute Flaccid Myelitis (AFM), a disease that causes sudden arm or leg weakness, and in some cases can lead to permanent paralysis. The CDC reports that so far in 2018, there have been 72 confirmed cases of AFM among a total of 191 cases currently under investigation.
But what’s causing it? And more importantly, how can we prevent it from happening to our children? Here’s what parents need to know:
AFM Peaks During Back-to-School Periods
During the past five years, surveillance data reported by the CDC shows a seasonal peak in juvenile cases of acute flaccid myelitis (AFM) in three of the years (2014, 2016, 2018), with the peak occurring in the month of September and the next higher levels of cases seen in the immediately adjacent months. Read on to learn about the relationship between these seasonal peaks and the back-to-school period.
Assuming the 3 peaks are non-random and related to some common phenomena, it’s noteworthy that these peaks coincide with the back-to-school period. Could this pattern involve some action which typically occurs during or immediately prior to the back-to-school period? The initial spike in case numbers in August implies that the increase in AFM cases probably isn’t related to disease transmission risks associated with increased exposure to groups of unfamiliar children when school typically starts, in early September. Instead, there’s an implication that actions in July-August have an effect that materializes and peaks one to two months later. The suspected actions then tail-off in a seasonal fashion, leading to the significant decline in cases from November onward.
AFM and the Two-Hit Theory
A plausible explanation for the seasonal peaks in AFM incidence is that some cases of AFM are dependent upon a “two-hit” or “three-hit” phenomenon, each one with an unlikely probability of occurring, thereby yielding a very low probability of all occurring together in a one person. While the first hit is necessary, it is the timing of the second or third hit which would determine the ultimate time point for the onset of a case of AFM, probably with a one to two month lag, considering the concentration of cases in the three month period of August-October.
The first hit, as widely acknowledged in case reports, could be an exposure to enterovirus such as EV-D68 and EV-A71, both linked to incidence of AFM by the CDC(1). Researchers have puzzled over the failure to identify the presence of either of these two virus strains in some AFM cases. A possible explanation for the lack of detection of these viruses is the presence of the virus at undetectable levels or its presence in cells that aren’t adequately sampled for testing. It’s notable that coxsackie viruses CVB3, a close relative of the two enterovirus strains linked to AFM and is also linked to paralysis, is reported to establish infection within cells of the immune system, similar to poliovirus (2,3). Consequently, a low-level enterovirus infection may exist in people believed to have “cleared” their infection.
For some, an enterovirus infection may therefore never completely disappear. Instead, the virus can reside in the immune cells known as B-cells, which produce antibodies against pathogens and sometimes circulate throughout the body as part of immune surveillance. B-cells with the marker CD19 have been observed to carry poliovirus and enterovirus and these cells can circulate through the body and can localize to sites of internal injury (4,5).
The second hit could be an intramuscular injection of drugs or vaccines into the arm or the leg that serves as a stimulus for B-cell migration to the injection site. Intramuscular injections cause mild tissue trauma that naturally attracts immune cells, sometimes producing slight swelling known as an injection site reaction. An enterovirus carrier who has virus residing in B-cells may thereby be susceptible to “provocation paralysis”, a phenomenon that has been observed in recipients of oral polio vaccine (attenuated, live virus) who subsequently received intramuscular injections of penicillin, quinine or DPT vaccine (6,7,8,9). Other modes of sustaining muscle tissue damage could include a mild trauma such as a fall or blunt force hit, which could result in bruised muscle that becomes inflamed, provoking a mild immune response that includes B-cell migration. Muscle tissue damage is significant as a risk factor for enterovirus linked paralysis because damaged muscle has increased numbers of enterovirus (CAR) receptors on cell surfaces as part of the healing response (CAR—coxsackie and adenovirus receptor). Hence, increased presence of CAR would logically increase the probability of enterovirus attachment to damaged muscle. B-cells carrying enterovirus that localize to injection or trauma sites could then release enterovirus into damaged muscle and into nerve tissue via the motor end-plate, providing access to the CNS (spinal cord) for the virus (10,11). Like CAR, the poliovirus receptor PVR is similarly found in muscle and at the motor end-plate(12).
While intramuscular injections of drugs or vaccines into arm or leg sites post administration of oral (live) polio vaccine have infrequently resulted in provocation polio paralysis, it seems especially significant that early signs of paralysis in provocation polio cases are often first observed in the limb that received an injection(7). A reasonable conclusion is that the same phenomenon observed for poliovirus, an enterovirus, could occur with other members of the enterovirus family such as EV-D68 and EV-A71.
What does this mean for parents?
AFM cases may occur in enterovirus “carriers” who experience a muscle injury from injection, trauma, or blunt force hit. Suspected AFM cases should have statistically meaningful samples of white blood cells that include CD19+ B-cells tested for the presence of enterovirus.
To reduce your child’s risk of contracting AFM, consider avoiding intramuscular injections and muscle trauma during and 1-2 months after a known outbreak of AFM-linked enterovirus strains in the community.
1. About Non-Polio Enteroviruses, CDC
2. “Furthermore, in peritoneal lavage, poliovirus was also present in CD19(+) B cells, but not in dendritic or T cells.” Pathogenesis of poliovirus infection in PVRTg mice: poliovirus replicates in peritoneal macrophages.
J Gen Virol. 2003 Oct;84(Pt 10):2819-28.
3. “Moreover, CVB3 also infects immune cells like CD19+ B lymphocytes, but the viral uptake mechanism into these cells is not well understood.” Antibody-dependent enhancement of coxsackievirus B3 infection of primary CD19+ B lymphocytes.
Viral Immunol. 2010 Aug;23(4):369-76.
4. “However, recent studies show that Type B coxsackievirus (CVB) infects B lymphocytes soon after infection, suggesting the possibility that these cells may play some role in virus dissemination and/or that the virus may be able to modulate the host immune response.” The role of B lymphocytes in coxsackievirus B3 infection.
Am J Pathol. 1999 Oct;155(4):1205-15.
5. “CVB3 replicated effectively in leukocytes of B-cell, T-cell, and monocyte origin, CVA24 in leukocytes of B-cell and monocyte origin...These findings suggest that the susceptibility of human leukocytes to non-polio EVs may be responsible for virus transport during the viremic phase, particularly to secondary target organs, and that active replication of CVB3 in all human leukocyte lineages leads to greater dissemination, in agreement with the ability of CVB to cause systemic diseases.” Characterization of infections of human leukocytes by non-polio enteroviruses.
6. “The risk of paralytic disease was strongly associated with injections given after the oral polio virus vaccine, but not with injections given before or at the same time as the vaccine (matched odds ratio, 56.7; 95 percent confidence interval, 8.9 to infinity)...we estimate that 86 percent of the cases of vaccine-associated paralytic poliomyelitis in this population might have been prevented by the elimination of intramuscular injections within 30 days after exposure to oral poliovirus vaccine...Provocation paralysis, previously described only for wild-type poliovirus infection, may rarely occur in a child who receives multiple intramuscular injections shortly after exposure to oral poliovirus vaccine, either as a vaccine recipient or through contact with a recent recipient. This phenomenon may explain the high rate of vaccine-associated paralytic poliomyelitis in Romania, where the use of intramuscular injections of antibiotics in infants with febrile illness is common.” Intramuscular injections within 30 days of immunization with oral poliovirus vaccine--a risk factor for vaccine-associated paralytic poliomyelitis.
N Engl J Med. 1995 Feb 23;332(8):500-6.
7. “Two-thirds of the paralytic cases but only 11% of the comparison group had been ill, visited a medical facility, and received multiple injections, primarily with quinine and penicillin, in the month prior to the onset of poliomyelitis. There was a strong temporal relationship between these injections and the onset of paralysis.” Injections and paralytic poliomyelitis in tropical Africa.
Bull World Health Organ. 1980;58(2):285-91.
8. “The authors reported the case of a AFP, occurring after a polio vaccination in a 5-year-old boy who had later an acute rhinopharyngitis treated by antibiotics and quinine intramuscular injections. A left lower limb AFP justified his hospitalisation.” [Acute flaccid paralysis after drug injection: a case report in the pediatric service of the Befelatanana Hospital Center in Antananarivo].
Arch Inst Pasteur Madagascar. 2000;66(1-2):58-60.
9. “The proportion of poliomyelitis cases that may have been provoked by DTP injections was 35% for children 5-11 months old. This study confirms that injections are an important cause of provocative poliomyelitis.” Attributable risk of DTP (diphtheria and tetanus toxoids and pertussis vaccine) injection in provoking paralytic poliomyelitis during a large outbreak in Oman.
J Infect Dis. 1992 Mar;165(3):444-9.
10. “In morphologically normal human muscle fibers, CAR immunoreactivity was limited to the neuromuscular junction. In regenerating muscle fibers, CAR was abundantly co-expressed with markers of regeneration.” Localization of coxsackie virus and adenovirus receptor (CAR) in normal and regenerating human muscle.
Neuromuscul Disord. 2005 Aug;15(8):541-8.
11. “We demonstrate a single isoform of CAR to be expressed exclusively at the human neuromuscular junction whereas both predominant CAR isoforms are expressed at the intercalated discs of non-diseased human heart.” Isoform-specific expression of the Coxsackie and adenovirus receptor (CAR) in neuromuscular junction and cardiac intercalated discs.
BMC Cell Biol. 2004 Nov 8;5(1):42.
12. “We found weak expression of PVR in the motor neurons but not the axons. In normal muscle, PVR was expressed at the end plate as confirmed by immunolocalization in serial sections with alpha-bungarotoxin. In neurogenic conditions and in myopathies, PVR was found in occasional denervated muscle fibers and in several regenerating ones. Human myotubes expressed PVR and were susceptible to the poliovirus infection. We conclude that PVR is present at the motor end-plate that can serve as one of the routes of entry of the virus to the motor neurons. The presence of PVR in the regenerating muscle fibers is in accord with clinical observations that muscle injuries can predispose patients to paralytic poliomyelitis.” Expression of poliovirus receptor in human spinal cord and muscle.
Ann N Y Acad Sci. 1995 May 25;753:48-57.
13. “A yeast two-hybrid screen was used to identify Ligand-of-Numb protein-X (LNX) as a binding partner to the intracellular tail of CAR. LNX harbors several protein-protein interacting domains, including four PDZ domains...We speculate that CAR and LNX are part of a larger protein complex that might have important functions at discrete subcellular localizations in the cell.” The Coxsackievirus and adenovirus receptor (CAR) forms a complex with the PDZ domain-containing protein ligand-of-numb protein-X (LNX).
J Biol Chem. 2003 Feb 28;278(9):7439-44.
14. “Many of these interactions suggest additional roles for LNX1/2 proteins in the nervous system in areas such as synapse formation, neurotransmission and regulating neuroglial function.” LNX1/LNX2 proteins: functions in neuronal signalling and beyond
Neuronal SignalingJun 07, 2018,2(2)NS20170191;
Paul W. Young
15. “Our histological investigations during development reveal an initial uniform distribution of CAR on all neural cells with a concentration on membranes that face the margins of the nervous system...Blocking antibodies were found to inhibit neurite extension in retina organ and retinal explant cultures...We observed a promiscuous interaction of CAR with extracellular matrix glycoproteins..." The coxsackievirus-adenovirus receptor reveals complex homophilic and heterophilic interactions on neural cells.
J Neurosci. 2010 Feb 24;30(8):2897-910.
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