Clinical Guidance for the Acute Medical Treatment of AFM

Notes and disclaimers

Clinicians should be aware that symptoms of AFM can initially be subtle and often mimic other neurologic diseases with targeted treatments.

This guidance is not intended to be generalized to all forms or etiologies of acute flaccid paralysis, such as Guillain-Barré syndrome, transverse myelitis, or other immune-mediated etiologies. If an alternative diagnosis for the acute flaccid paralysis is under consideration, all efforts should be made to explore the alternative diagnosis, and if found, appropriate treatment should be rendered. The clinical guidance below reflects a review of available scientific literature on AFM and individual input from subject matter experts.

Disclaimer: The use of the drug names is for informational purposes only, and does not imply endorsement or criticism of the product or manufacturer by the U.S. Government, the Department of Health and Human Services, or the Centers for Disease Control and Prevention. The information provided is not intended to be medical advice and should not supplant the consultation of one's personal physician.

Clinicians should immediately consult with their local neurologists and/or infectious disease specialists for treatment and medical management decisions for any suspected AFM patient. Clinicians can also contact neurologists specializing in AFM through the AFM Physician Consult and Support Portal to schedule a peer-to-peer consultation for clinical support.

Summary of Clinical Guidance

Based on the available evidence and individual input from experts:

• There is no indication that any specific targeted treatment should be either preferred or avoided in the acute medical treatment of AFM.
• There is currently no targeted treatment with enough evidence to endorse or discourage use for the treatment or management of AFM.
• There continues to remain a paucity of prospective clinical trials on treatments for AFM. Current sources are limited to case reports and case-series. Acute treatments that have been used frequently in patients with AFM include intravenous immunoglobulin, corticosteroids, and/or therapeutic plasma exchange.
• Clinicians should expedite neurology and infectious disease consultations to discuss treatment and management considerations.
• Intravenous immunoglobulin (IVIG): There is no indication that IVIG should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of IVIG in the treatment of AFM; evidence for efficacy is based on early treatment in animal models infected with enterovirus (EV) D68 and it has not been given in a systematic manner to AFM patients to allow for measurements of efficacy. There is no evidence that treatment with IVIG is likely to be harmful.
• Corticosteroids: There is no indication that corticosteroids should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of corticosteroids in the treatment of AFM, and there is some evidence in a mouse model with EV-D68 that corticosteroids may be harmful. The possible benefits of the use of corticosteroids to manage spinal cord edema or white matter involvement in AFM should be balanced with the potential harm due to immunosuppression in the setting of possible viral infection.
• Therapeutic plasma exchange (TPE): There is no indication that therapeutic plasma exchange should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of plasma exchange in the treatment of AFM, and it has not been given in a systematic manner to AFM patients to allow for measurements of efficacy. Although there are inherent procedure-associated risks, there is no evidence that using plasma exchange for patients with AFM is likely to be harmful.
• Fluoxetine: There is no indication that fluoxetine should be used for the treatment of AFM.
• Antiviral medications: There is no indication that currently available antivirals should be used for the treatment of AFM.
• Interferon: There is no indication that interferon should be used for the treatment of AFM.
• Other immunosuppressive medications/biological modifiers: There is no indication that the use of other immunosuppressive agents or biologic modifiers should be used for the treatment of AFM.

Background

In October 2014, CDC developed a document containing considerations for the clinical management of children with clinically diagnosed AFM. CDC solicited AFM subject matter experts across a range of disciplines to provide individual expert opinion on this document. These experts were chosen from the fields of infectious diseases, neurology, pediatrics, critical care medicine, public health epidemiology, and virology. The opinions from these individual consultations formed the basis of the "Interim Considerations for Clinical Management of AFM" document, developed in 2014 and updated in 2018 (1). In January 2020, CDC conducted an additional review of published literature on AFM from 2014-2020, focusing on the acute medical treatments that have been used in patients with AFM. This literature review did not reveal any additional clinical trials on treatments specifically for AFM. This systematic approach for reviewing published literature will be updated at least annually and when new data become available.

There continues to remain a paucity of published evidence on acute medical treatments for AFM and lack of controlled human studies to assess the safety and efficacy of these treatments (2-4). Consultation with experts treating AFM patients remains essential and further AFM research is critical.

Thus, guidance regarding these initial pharmacologic treatments should be interpreted with caution, given the present unknowns about the pathogenesis of AFM and efficacy of these specific acute medical treatments in humans. CDC is working with health departments, other federal agencies, researchers, and hospitals/academic entities to improve our understanding of AFM and the use of medical drugs/biologics for this condition.

Specific Acute Medical Treatments

Intravenous Immune Globulin (IVIG)

Summary: There is no indication that IVIG should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of IVIG in the treatment of AFM; evidence for efficacy is based on early treatment in animal models directly infected with EV-D68 and it has not been given in a systematic manner to AFM patients to allow for measurements of efficacy. There is no evidence that treatment with IVIG is likely to be harmful.

1. IVIG has been utilized for neurologic complications in enteroviral disease associated with neurologic involvement. Enteroviruses cause chronic, severe central nervous system (CNS) infections in agammaglobulinemic children, suggesting humoral immunity plays an important role in attenuating enteroviral infection (5). Similarly, infants who fail to acquire neutralizing antibodies from their mothers have been described as having more severe disease when infected with enteroviruses (6).
2. IVIG has been shown to modulate cytokine production (i.e., IFN-γ, IL-6, IL-8, IL-10, IL-13) in the CNS and the systemic inflammatory response. In addition, there is a theoretical risk of IVIG interfering with naturally acquired innate immunity, due to the immunomodulatory effects of the F(ab') region of the immunoglobulin molecule, which may impact cell-mediated immunity.
3. For IVIG to modify disease in an active viral infectious process, early administration is likely required, and possibly prior to exposure. Pre-poliovirus vaccine era trials in the 1950s demonstrated potential efficacy of gamma globulin for prevention of poliomyelitis with mass gamma globulin administration to susceptible populations in an outbreak situation (7,8). However, a randomized, non-blinded trial of intramuscular (IM) gamma globulin treatment in 49 children (48 controls) with pre-paralytic poliomyelitis (i.e., CSF WBC>10 cells/mm without development of weakness) did not impact development or severity of paralysis during a poliovirus outbreak in New York City in 1944 (9).
4. IVIG has been shown to have some efficacy in prevention of progression to neuroinvasive disease in rodent models (10,11,12). Paralysis in mice was prevented after administration of IVIG in a time-dependent fashion from time of infection.
5. There has been experience with the use of IVIG in the treatment of neuroinvasive disease associated with West Nile virus (WNV) and EV-D68. However, clear efficacy of IVIG has not been demonstrated in humans with WNV-associated paralysis, with most data limited to case reports or small case-series (13,14)
6. IVIG has been utilized for patients presenting with symptoms of AFM, but to date no systematic studies of IVIG have been conducted. Recent reviews on the clinical management of AFM patients have noted that IVIG has been frequently utilized in many centers in the hope of boosting humoral immunity (2,3). In the 2014 – 2015 case-series, treatment of AFM using IVIG was done either alone or in combination with methylprednisolone and therapeutic plasma exchange. All patients tolerated the treatment regimens well without major complications. Neurologic improvement was seen in all patients regardless of treatment, but in all except one patient, deficits persisted (15). Messacar et al. reported on a review of clinical cases from 2012 – 2015. All cohorts that were reviewed received various combinations of IVIG, corticosteroids, TPE, and antiviral medications. No significant improvement or deterioration was noted with these therapies, but a systematic assessment of response was not feasible with the retrospective review (16).
7. IVIG is generally safe and well tolerated. Common intra-infusion adverse effects of IVIG include fever, headache, myalgia, chills, nausea, and vomiting, which are typically infusion rate-dependent (17). Less commonly, hypersensitivity and anaphylactoid symptoms of flushing, tachycardia, and hypotension can be seen. Post-infusion adverse events include headaches and aseptic meningitis, fatigue, and arthralgias (18). IVIG is occasionally associated with severe adverse events such as acute renal failure, thromboembolic events, hemolytic anemia, and neutropenia.
8. IVIG preparations have been shown to contain antibody to circulating enteroviruses, including EV-D68 (19).

Corticosteroids

Summary: There is no indication that corticosteroids should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of corticosteroids in the treatment of AFM, and there is some evidence in a mouse model with EV-D68 that corticosteroids may be harmful. The possible benefits of the use of corticosteroids to manage spinal cord edema or white matter involvement in AFM should be balanced with the possible harm due to immunosuppression in the setting of possible viral infection.

1. Corticosteroids have been given in several published case-series and reports of AFM patients, but most often in combination with other therapies such as IVIG and plasma exchange, making it difficult to assess their effects on the disease process (15,16, 20).
2. There is a theoretical concern about the possible adverse effects of administration of corticosteroids in the setting of acute infection, which may compromise the innate immune response to the infection, thus propagating the infectious process and leading to further neuronal damage and worse clinical outcomes.
3. The use of corticosteroids has been associated with poorer outcome in observational studies of outbreaks of neuroinvasive disease due to enterovirus A71 (EV-A71) internationally and in mouse models (21,22). This observation, following a 2012 outbreak in Cambodia, led to the conclusion among a WHO-convened joint commission that corticosteroids were contraindicated in the management of EV-71 associated neuroinvasive disease (23). This is relevant, as EV-A71-associated neurologic disease was reported in the United States in 2018.
4. In a mouse model of AFM with EV-D68 directly injected into an extremity, mice receiving dexamethasone at either early or late time points from infection had significantly higher mortality compared to infected controls. Individual dexamethasone-treated mice that died had more severe paralysis measured by their motor impairment score than in an infected control (10).
5. There may be theoretical benefit of corticosteroids in the setting of severe cord swelling or long tract signs suggesting white matter involvement, where corticosteroids may salvage tissue that may be harmed due to an ongoing immune/inflammatory response. While AFM is clinically and radiographically defined by the predominance of gray matter damage in the spinal cord, some patients may have some white matter involvement (24). It is not clear if these different patterns are important relative to therapeutic considerations.
6. The differential diagnosis for AFM includes conditions that would best be treated by early initiation of corticosteroids (i.e., transverse myelitis, anti-MOG antibody related disease, acute disseminated encephalomyelitis).

Therapeutic Plasma Exchange (TPE)

Summary: There is no indication that therapeutic plasma exchange should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of TPE in the treatment of AFM, and it has not been given in a systematic manner to AFM patients to allow for measurements of efficacy. Although there are inherent procedure-associated risks, there is no evidence that using therapeutic plasma exchange for patients with AFM is likely to be harmful.

1. It is presumed that there are beneficial effects from the humoral immune response to an acute viral infection, in which the body produces neutralizing antibodies to the infectious pathogen (25). Theoretically, the removal of these antibodies induced in response to acute infection could cause potential harm. Additionally, therapeutic plasma exchange requires placement of invasive intravenous access and poses procedure-associated risks.
2. Therapeutic plasma exchange has been used in several published observational studies of AFM patients. From a case-series in Argentina, 4 children were given TPE in combination with IVIG and steroids. Treatment did not lead to clinical improvement (26). A longitudinal study in Canada used TPE in 10 children in conjunction with IVIG and/or corticosteroids and showed clinical improvement upon long-term follow up of at least up to 18 months post-onset (27). In a single AFM case published in 2017, Esposito et al. treated a 4-year-old child with TPE in addition to corticosteroids and IVIG for 3 days. After 4 weeks of oral corticosteroids and a 2-week taper, significant improvement was noted (20). No serious adverse events were noted for TPE in the above publications.

Fluoxetine

Summary: There is no indication that fluoxetine should be used for the treatment of AFM. There is no clear human evidence for efficacy of fluoxetine in the treatment of AFM based on a multicenter non-randomized, retrospective study conducted in patients with AFM (28), and data from a mouse model do not support efficacy (10).

Antiviral medications

Summary: There is no indication that currently available antivirals should be used for the treatment of AFM unless there is suspicion of other viral infections with targeted treatment. Testing has been conducted at CDC for antiviral activity of compounds such as pleconaril, pocapavir, and vapendavir, and none have significant activity against currently circulating strains of EV-D68 at clinically relevant concentrations (29).

Interferon

Summary: There is no indication that interferon should be used for the treatment of AFM, and there is concern about the potential for harm from the use of interferon given its immunomodulatory effects in the setting of possible ongoing viral replication. There are limited in vitro, animal, and anecdotal human data suggesting activity of some interferons against viral infections; however, sufficient data are lacking in the setting of AFM (30,31).

Other immunosuppressive medications / biological modifiers

Summary: There is no indication that the use of other immunosuppressive agents and biologic modifiers should be used for the treatment of AFM at this time. In the setting of AFM, biologic modifiers may have an adverse impact on patients, presuming infectious etiology. The combination of immunosuppressive agents directly impairing T-cell function (and B-cell function indirectly), or therapy directed against primary humoral immunity (e.g., rituximab) may theoretically further worsen the ability to clear infection.

References

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