Review Article Influenza vaccination and Guillain– Barré syndrome: Reality or fear Arefeh Babazadeh1, Zeinab Mohseni Afshar2, Mostafa Javanian1, Mousa Mohammadnia-Afrouzi1, Ahmad Karkhah3, Jila Masrour-Roudsari1, Parisa Sabbagh1, Veerendra Koppolu4, Veneela KrishnaRekha Vasigala5, Soheil Ebrahimpour1 1Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, I.R. Iran; 2Zeinab Mohseni Afshar, Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran; 3Student Research Committee, School of Medicine, Babol University of Medical Sciences, Babol, Iran; 4Scientist Biopharmaceutical Development Medimmune Gaithersburg, MD 20878, USA; 5Rangaraya Medical College, NTR University of Health Sciences, Kakinada, India ABSTRACT Guillain–Barré syndrome (GBS) is an inflammatory disorder and an acute immune-mediated demyelinating neuropathy that causes reduced signal transmissions, progressive muscle weakness, and paralysis. The etiology of the syndrome still remains controversial and uncertain. GBS can be initiated and triggered by respiratory tract infections such as influenza, and intestinal infections such as Campylobacter jejuni. In addition, there is considerable evidence suggesting links between influenza vaccination and GBS. As reported previously, the incidence of GBS in individuals receiving swine flu vaccine was about one to two cases per million. Despite the influenza vaccine efficacy, its association with an immune-mediated demyelinating process can be challenging as millions of people get vaccinated every year. In this review we will discuss the association between influenza infection and vaccination with GBS by focusing on the possible immunopathological mechanisms. Key words: influenza, flu vaccination, Guillain–Barré syndrome INTRODUCTION GUILLAIN–BARRÉ SYNDROME: SYMPTOMS Guillain–Barré syndrome (GBS) is a rare AND CAUSES immune disorder in which the immune Address for Correspondence: Dr. Soheil Ebrahimpour, Infectious system invades Schwann cells of the Since the eradication of polio, GBS has Diseases and Tropical Medicine [1-3] Research Center, Health Research peripheral nervous system (PNS). The become the most common cause of acute Institute, Babol University of Medical etiology of GBS is still unclear. Recent Sciences, Babol, Iran. flaccid paralysis. GBS is an autoimmune E-mail: [email protected] investigations demonstrated that GBS can disorder affecting the Schwann cells of the be triggered by several respiratory tract PNS. This immune-mediated demyelinating Access this article online and intestinal infections. A significant neuropathy can rapidly evolve over a period Website: number of GBS cases were also inflicted of few days or more and can lead to paralysis www.intern-med.com by Zika virus infection. After a large-scale or even death.[5-7] The initial symptoms of DOI: 10.2478/jtim-2019-0028 vaccination campaign in 1976 against swine GBS include muscle weakness that starts Quick Response Code: influenza, an increase in the incidence from distal limbs which subsequently of GBS was noticed and thus raising progresses to proximal limbs.[8] GBS the doubts on the safety of influenza may lead to respiratory failure requiring vaccination.[4] Subsequently, many studies mechanical ventilation over 15% of cases.[9] were performed to evaluate the association In some cases, GBS can affect the heart of infections and in particular influenza rate and changes the blood pressure by as well as influenza vaccination with an disrupting the autonomic nervous system.[10] incidence of GBS. The disease can be self-limiting, with muscle JOURNAL OF TRANSLATIONAL INTERNAL MEDICINE / OCT-DEC 2019 / VOL 7 | ISSUE 4 137 Babazadeh et al.: Influenza vaccination and Guillain–Barré syndrome strength reaching a lowest point in few days, followed by a either a Th1 (T helper cell type 1) or Th2 phenotype. Each partial or full recovery over weeks to months. Diagnosis of phenotype has its specific cytokine signature and function. this syndrome is based on the clinical signs and symptoms Once inside the PNS, the Th1 phenotype of differentiated and through rule out of other differential diagnoses as Th cell recruits and activates macrophages. Macrophages shown in Table 1. The treatment includes administration initiate damage to PNS by producing and secreting matrix of intravenous immunoglobulins or plasmapheresis, and metalloproteinases (MMPs) and nitric oxide.[26] Humoral supportive therapies. Although most people have an responses are initiated through activation of B cells by Th2 uneventful recovery, up to one-third of the cases are left lymphocytes or by the epitopes of the virus cross-linking [11, 12] with severe neurological deficits. The mortality rate the B cell receptors. Both these pathways can result in class of the disease is approximately 8% in developing world, switching of activated B cells to IgG-producing plasma [13] but much lower in developed countries. The incidence cells. The secreted IgG binds to viral surface epitopes of GBS increases with age, and people older than 50 years and cross-reacts with similar epitopes in the peripheral are at greatest risk for developing GBS. The estimated nervous tissues. These antigen–antibody interactions can risk of developing GBS in the world is one to two cases activate the complement system, resulting in membrane [14] per 100,000 people per year. Severe autoimmune attack complex (MAC) formation [27] leading to nerve cell responses resulted from infections by external infectious membrane damage and destruction.[28] agents are considered as major initiating factors of the [15, 16] syndrome. Infection by Campylobacter jejuni is identified INFLUENZA AND ITS as the most common inciting event although other agents COMPLICATIONS such as herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), Zika virus (ZIKV), Influenza is a highly contagious respiratory infection that is Mycoplasma pneumoniae, Haemophilus influenza, and influenza [29] [7, 17-22] common in cold seasons. Annually, influenza epidemics have been reported. Vaccination to influenza has been cause 3–5 million severe cases of hospitalization and implicated in GBS, although the evidence for this link is 300,000–600,000 deaths.[30, 31] controversial.[23] Typical symptoms of influenza infection include fever with IMMUNOPATHOLOGY OF GUILLAIN– shaking chills, myalgia, fatigue, anorexia, and diarrhea. The BARRÉ SYNDROME severity of these symptoms and their sudden occurrence can help differentiate influenza from other respiratory Access to the PNS by the immune system requires crossing viral infections.[29,32,33] Symptoms such as cough and sore of the blood–nerve barrier. The blood–nerve barrier is not throat are prevalent in influenza; however symptoms such as tight as the blood–brain barrier, so that small amounts as coryza are more due to common cold infections than of circulating proteins and immunoglobulin G (IgG) influenza infection.[34] Influenza viruses are divided into can leak into PNS making it vulnerable to the immune influenza A, B, and C types. Influenza A and B viruses attacks. The blood–nerve barrier is particularly leaky circulate in the community in the winter every year and within the dorsal root ganglia and is altogether absent at are found to be responsible for seasonal epidemics.[35] nerve terminals, making these areas especially vulnerable Influenza C viruses usually have no symptoms or show to immune-mediated attacks. As previously mentioned, mild symptoms and do not cause epidemics.[36] Mutations GBS begins with infectious agents such as influenza in the influenza viral genomes leading to antigen changes virus. Antigen-presenting cells (APCs) including dendritic (shift or drift), as well as the existence of animal reservoirs, cells (DCs), macrophages, and B lymphocytes are in the can make the influenza treatment challenging as public frontline dealing with the influenza infections.[24, 25] Epitopes immunity from previous immunizations may not be enough displayed by the virus interact with pattern recognition for protection.[37] In some instances the changes to the viral receptors (PRRs) on APCs, especially DCs. Stimulation of genomes are so intense that the existing vaccines may no APCs results in T cell activation and differentiation into longer be effective leading to pandemics, such as a late Table 1: Some diagnostic criteria in Guillain–Barré syndrome. Criteria for diagnosis of Guillain–Barré syndrome Required Weakness within 4 weeks from onset of syndrome (starting muscle weakness in lower limbs) Hyporeflexia Supportive Lack of fever in the patient Infections of the respiratory and gastrointestinal system during the past few weeks Increased protein concentration in cerebrospinal fluid (CSF) with moderate increase in the cell 138 JOURNAL OF TRANSLATIONAL INTERNAL MEDICINE / OCT-DEC 2019 / VOL 7 | ISSUE 4 Babazadeh et al.: Influenza vaccination and Guillain–Barré syndrome winter outbreak of swine flu (pH1N1) in 1976 and flu relative risk for the incidence of GBS after influenza pandemic or swine flu in 2009 (caused by influenza A virus vaccination was 1.4 (95% CI: 1.2–1.7).[4] Other studies type pH1N1).[38] The complications of influenza infection investigating the association between GBS and seasonal can be either mild or very severe. Sinusitis and otitis are influenza vaccines after 1976 indicated the risk as very examples of moderate complications of influenza.[39]