Immunological Investigations, 2014; 43(3): 292–298 ! Informa Healthcare USA, Inc. ISSN: 0882-0139 print / 1532-4311 online DOI: 10.3109/08820139.2013.859156

Mohammadreza Shaghaghi,1 Nima Parvaneh,1 Pouya Ostad-Rahimi,1 Seyed Mohammad Fathi,1 Shohreh Shahmahmoodi,2 Hassan Abolhassani,1 and Asghar Aghamohammadi1 1

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Science, Tehran, Iran, 2 Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran Neurologic abnormalities compatible with vaccine-related poliovirus infection (VAPP) may be a first presentation of some primary immunodeficient patients. The risk of VAPP rises from 1 case per 750 000 in normal population to 1 per 7000 times higher, particularly for persons with agammaglobulinemia and hypogammaglobulinemia. However, there is no appropriate estimation for VAPP occurrence in patients with cellular immunity defects. Herein we report a case of combined immunodeficiency with paralytic complication due to oral polio vaccine and we present a literature review on this topic. Keywords Combined immunodeficiency, panhypogammaglobulinemia, poliovirus, vaccination

INTRODUCTION Since the launch of the global polio eradication initiative in 1988, billions of oral polio vaccine (OPV) doses have been distributed worldwide, leading to marked decrease in polio infections (CDC, 2012a; Dowdle et al., 2003). OPV is administered easily with extremely rare adverse events. Vaccineassociated paralytic poliomyelitis (VAPP) is the most commonly recognized severe complication of OPV (Kew et al., 2005). The approximate rate of VAPP is one case per 6.2 million OPV administered doses (CDC, 2003). Following replication in human gut, the attenuated vaccine strain poliovirus might revert to a neurovirulent phenotype. These vaccine-derived polioviruses (VDPVs) can affect OPV recipients or their contacts (Davis et al., 1977, Wright et al., 1977). Primary immunodeficient patients are at a distinguishable higher risk of VAPP than the normal population (Rosen et al., 1995). Likewise, these patients are more likely to

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Combined immunodeficiency presenting with vaccine-associated paralytic poliomyelitis: a case report and narrative review of literature

Correspondence: Asghar Aghamohammadi, Children’s Medical Center Hospital, 62 Qarib St., Keshavarz Blvd., Tehran 14194, Iran. E-mail: aghamohammadi@sina.


carry and excrete the vaccine-associated virus for a long time (immunodeficiency-related VDPV [iVDPV]), which could serve then as a possible reservoir for reintroducing the neurovirulent strains into the population (Khetsuriani et al., 2003). The genetically drifted VDPV may also circulate in immunocompetent individuals of undervaccinated communities (circulating VDPVs [cVDPVs]) (Alexander et al., 2009, Kew et al., 2005).

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CASE REPORT The patient is a 19-month-old boy, the first child of consanguineous parents (first cousins) with normal perinatal conditions. His parents were healthy, and there was no condition indicating an immunodeficiency state in the relatives. He underwent a routine national vaccination schedule, receiving 3 doses of OPV at birth, 2 and 4 months of age. Tetanus, diphtheria, pertussis (Tdap) vaccine at ages 2 and 4 months were administered. Bacillus Calmette– Gue´rin (BCG) and Hepatitis-B vaccine were also taken during first week after birth. He had been quite healthy until 6 months of age, when he developed chronic diarrhea and right paraparesis. The patient was admitted to Children’s Medical Center affiliated to Tehran University of Medical Sciences, Tehran, Iran. Physical examination revealed a febrile boy presenting flaccid paresis of the right leg with impaired tendon reflexes and plantar response. Upper limbs and the left lower extremity were normal. No lymphadenopathy or organomegaly was notable. Further evaluations showed the absence of tonsils and diffuse candidiasis of oral cavity. At baseline, he had mild anemia and lymphopenia. Laboratory analysis of serum immunoglobulins indicated panhypogammaglobulinemia with reduced levels of both naive and specific antibodies. Diminished CD3, CD4 and CD19 cells were manifested in flow cytometry with an inversion of CD4/ CD8 T-cell ratio. Lymphocyte transformation tests were normal and the other serologic tests as well (Table 1). Stool examination showed Salmonella group C infection. Polio culture was performed in the Iranian National Polio Laboratory (NPL), and all serially collected specimens yielded Sabin 2 virus. A diagnosis of cellular immunodeficiency with consequent VAPP was made and regular Intravenous immunoglobulin (IVIG) transfusion, at the dosage of 500 mg/kg every 4 weeks was introduced. The patient also commenced on prophylactic antimicrobial therapy and physical therapy. Within 1 month of IVIg initiation, diarrhea was relieved and treatment continued regularly. At 17 months of age, the patient was hospitalized with poor general condition and respiratory distress. Bilateral alveo-interstitial involvement was evident in chest radiography. Spiral high resolution computed tomography of lungs featured a ground glass appearance in the bilateral perihylar regions and upper lobes with an alveolar pattern of involvement. The findings were suspicious for severe aspiration pneumonia or atypical pneumonitis. Analysis of bronchoalveolar lavage fluid evinced the aggregation of foamy materials, suggesting the diagnosis of pneumocystis infection; however, polymerase chain reaction was just weakly positive for Herpes simplex virus genome. The patient was placed on a combination of Ceftazidime, Vancomycin and sulfamethoxazole-trimethoprim (ST). His condition improved after intensive antibiotic treatment completion. From age 6 months to 19 months, follow-up



M. Shaghaghi et al. Table 1. Laboratory data of a case with combined Immunodeficiency and vaccine-associated paralytic poliomyelitis.

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Test WBC (cells/ml) Hb (mg/dl) Platelets (cells/ml) ALC (cells/ml) CD3 % of ALC CD4 % of ALC CD8 % of ALC CD19 % of ALC CD16–56 % of ALC IgG (mg/dl) IgM (mg/dl) IgA (mg/dl) IgE (IU-ml) Anti-diphtheria (mg/dl) Anti-tetanus (mg/dl) LTT (SI): PHA BCG Candida


Normal range

6050 9.3 473 1040 50.7 19.82 25.39 1.05 32.17 30 22 6 0 0.0 0.0

6400–13 000 10–14 4150 000 3400–9000 50–77 33–58 13–26 13–35 2–13 172–1069 33–126 11–106

3.22 2.75 2.95

43.0 42.5 42.5

40.1 40.1

WBC: White blood cell, Hb: hemoglobin, ALC: absolute lymphocyte count, CD: cluster of differentiation, Ig: immunoglobulin, LTT: lymphocyte transformation test, PHA: Phytohaemagglutinin test, BCG: Bacillus Calmette–Gue ´ rin test.

fecal cultures showed persistent shedding of Sabin type2 virus during this 13-month period. None of the patient’s relatives were found to be infected. The latter electrodiagnostic workup of the right leg indicated remote distal axonal neuropathy of deep peroneal nerve. The patient’s blood sample was analyzed for Bruton’s tyrosine kinase (BTK) mutation to assess the differential of X-linked agammaglobulinemia, but this evidenced no defect in the BTK gene. The final diagnosis of combined immunodeficiency was established. Based on the lymphopenia, immunophenotyping of this patients (T-B-NKþ) and absence of microcephaly or other clinical dysmorphism, the diagnosis of DNA ligase 4 and Cernunnos deficiency were ruled out for him, and he will be a candidate for evaluation of mutation in RAG1, RAG2, DCLERE1C (Artemis deficiency) and PRKDC (DNA PKcs deficiency) genes. Virologic studies Fecal specimens were sent to NLP, School of Public Health and Institute of Public Health research, Tehran University of Medical Sciences, Iran, which is a part of Global Polio Lab Network. Virus isolation and serotype identification were performed using the World Health Organization protocol for poliovirus detection in stool specimens of acute flaccid paralysis cases (WHO, 1997). Intratypic differentiation assays (enzyme-linked immunosorbent assay and polymerase chain reaction) investigated the vaccine-derived origin of the isolated virus. Thirteen stool specimens were forwarded monthly to NLP, which were all positive for polioviruses type 2 with 41% nucleotide divergence


from Sabin strain genome, confirming iVDPV. Genome sequencing of isolates was done by Centers for Disease Control and Prevention (CDC, Atlanta), which corresponded with those of the NLP.

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DISCUSSION Although OPV has been used efficiently worldwide, leading to a notable reduction in poliomyelitis cases within past 40 years (Kew et al., 2005), increased neuropathogenic potential of OPV strains represents a problem with respect to vaccine safety (Guillot et al., 2000). The virulent strain isolated from our patient was a Sabin-derived type 2 virus. Sabin type 2 and 3 are more likely to persist after OPV cessation and to be the causative agents of outbreaks (Sasaki et al., 2012). Sabin type 3 is associated with the highest rate of VAPP in immunocompetent patients, whereas type 2 has been the most prominent type of iVDPV (CDC, 2007; Kew et al., 2005). Almost all immunodeficient neonates are vaccinated with OPV at birth when their immunodeficiency state is not identified. There is a potential risk for these patients to both develop paralysis and excrete the vaccine strains for long periods (Mamishi et al., 2008). These patients can be asymptomatic before acute paralysis occurs and remain undetected in some occasions (Abo et al., 1979; Parvaneh et al., 2007). Our patient had received the first OPV dose at birth, and paresis occurred 2 months after administration of the third dose. He excreted VDPV strains for 13 months after the onset of flaccid paralysis and proper treatment could not clear the virus. However, none of his contacts shed the virus in stool. Long-term duration of polio virus excretion has been described up to 7.8 years (Khetsuriani et al., 2003; Shahmahmoodi et al., 2010). Although the risk for further transmission of iVDPV is relatively low (Shahmahmoodi et al., 2010), this long-term shedding of virulent strains from immunodeficient patients into the community remains a risk for re-emergence of the disease in future. In these circumstances, Sasaki et al. (2012) has estimated the probability of VDPV outbreaks more than 90% after OPV cessation. For the first time in a developed country, a transmission of VDPV was demonstrated in an undervaccinated community in the United States in 2005 (Alexander et al., 2009). Eight of 23 children of the community had evidences of infection with type 1 VDPV, which probably had circulated in the community for about 2 months before detection of the index case. Although all-inactivated poliovirus vaccine (IPV) strategy has been used in this country since 2000, the importation of iVDPV from another OPV-using country could be the possible source of infection (Alexander et al., 2009), which demonstrates the potential risk of iVDPV transmission. The second case of VDPV in United States was a non-imported paralytic poliomyelitis patient reported in 2011. She was a known case of common variable immunodeficiency. Interestingly, virologic studies showed that infection occurred almost 12 years earlier with VDPV type 2; that was consistent with the time when her child had been given the oral polio vaccine. This highlights the need for an accurate surveillance of VDPV and acute flaccid paralysis even in countries using IPV (DeVries et al., 2011).



M. Shaghaghi et al. Table 2. Outbreaks of circulating vaccine derived polioviruses worldwide, through 2012.

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Country Egypt Haiti Dominican republic Philippines Madagascar China Madagascar Indonesia Cambodia Myanmar Ethiopia Ethiopia India Chad* Afghanistan Madagascar Mozambique Yemen Niger* Somalia DRC** Nigeria


Total no. of specimens

VDPV serotype

1988–1993 2000–2001 2000–2001 2001 2002 2004 2005 2005 2005–2006 2006–2007 2008–2009 2009–2010 2009–2010 2010 2010–1011 2011 2011 2011 2006–2011 2008–2011 2008–2012 2005–2012

30 8 13 4 6 4 3 46 3 4 4 7 16 1 6 2 2 9 6 17 64 403

2 1 1 1 2 1 2 1 3 1 2 3 2 2 2 2 1 2 2 2 2 2

*Outbreaks in Niger and Chad caused by importation from Nigeria. **Democratic Republic of Congo.

As of 2012, circulating VDPVs produced at least 20 localized outbreaks (i.e., two or more polio cases) in OPV-using countries (Table 2) (Burns et al., 2013; CDC, 2006; CDC, 2007; CDC, 2011; CDC, 2012b; Dashti-Khavidaki et al., 2009). VDPV 2 has been the most common type in these emergences. The outbreaks in Niger and Chad were caused by importing from neighboring states in Nigeria. The outbreak in Nigeria has continued since 2005, which has been resolved into 23 independent VDPV 2 emergences. Detection of multiple concurrent circulating VDPV2 outbreaks in Nigeria highlights the risks of VDPV emergence accompanying trivalent-OPV use at low rates of coverage in developing countries (Burns et al., 2013), which poses a risk of transmission to other countries. Iranian polio eradication campaign was started in 1993 and has reached 100% coverage of 51 year-old infants in country. However, no case of indigenous wild poliovirus has been reported after 2001; several reports of vaccine-derived polio infections have been documented (Shahmahmoodi et al., 2010). Presentation of eight iVDPV cases during the past 17 years in Iran indicates the ongoing risk of VDPV emergence in OPV-using countries, beside the unclear number of unidentified virus shedders. As long as OPV is used, new VDPV infections will occur and no effective therapies to clear VDPV infections are available (CDC, 2012a). Nevertheless IPV immunization cannot prevent poliovirus re-infection (Murdin et al., 1996);


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it reduces the duration of viral excretion (Henry et al., 1966). It is crucial to reach a high level of trivalent-OPV coverage in developing countries to limit the transmission of wild or vaccine-related poliovirus as soon as possible. Thereafter, switching to IPV strategy with a high percentage of coverage seems mandatory to reduce VAPP cases and limit VDPV transmission in the future. Beside the importance of IPV initiation, a sensitive surveillance of the environmental samples and high-risk individuals such as immunodeficient or acute flaccid paralysis patients is crucial to detect and restrict the persistence of any vaccine-related virus in post-OPV eradication strategies.

DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Combined immunodeficiency presenting with vaccine-associated paralytic poliomyelitis: a case report and narrative review of literature.

Neurologic abnormalities compatible with vaccine-related poliovirus infection (VAPP) may be a first presentation of some primary immunodeficient patie...
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