Febrile #80 – Curious Congenital Conundrums – Viral Rival

September 25, 2023

Summary

Welcome to Febrile’s Curious Congenital Conundrums Part 2!! Drs. Fionnuala Ryan and Alasdair Bamford discuss a NICU consult for neonatal sepsis with hepatosplenomegaly, rash, and elevated ferritin

Credits

Hosts: Fionnuala Ryan, Sara Dong

Guest: Alasdair Bamford

Writing: Justin Penner

Producing/Editing/Cover Art: Sara Dong

Our Guests

Dr. Fionnuala (Finn) Ryan

Fionnuala Ryan (Finn) is currently a trainee in Paediatric Infectious Diseases in London. She completed her MBChB at the University of Manchester, UK and was awarded a distinction for her intercalated Masters degree in Humanitarianism and Conflict Response. In 2012-2014 she completed her foundation training in the southwest of England and subsequently worked as a clinical fellow in Adult Infectious Diseases in Bristol. Following a Paediatric registrar post in Christchurch Hospital, New Zealand, she completed her DTM&H at the Gorgas Institute in Lima, Peru in 2016. She started her Paediatric training in London in 2016 and completed her MRCPCH in 2018. During her registrar training, she explored her interest in teaching by working part-time as a Paediatric Education fellow and was awarded a post-graduate certificate in Medical Education (with distinction) from Queen Mary University of London. Fionnuala has a strong interest in global health, and has worked for NGOs in Nicaragua, Panama and returned in May from her most recent post working for Doctors Without Borders in Yemen. Outside of work she can be found training for a long cycle ride she volunteered to do in a misguided moment of self-belief. She usually enjoys cooking, learning Spanish and Arabic and planning her next holiday.

Dr. Alasdair Bamford

Alasdair Bamford is a Paediatric Infectious Diseases Consultant and Specialty Lead at Great Ormond Street Hospital for Children and an Honorary Associate Professor at UCL (University College London) GOSH (Great Ormond Street) Institute of Child Health, London, UK. His main interests include paediatric HIV and other blood borne viruses, infection in the immunocompromised host, central nervous system infection and the balance between infection and inflammation in conditions such as HLH. He is also a trial clinician a the MRC Clinical Trials Unit, London UK working on a number of paediatric infection related trials and cohort studies. He is a member of the Penta-ID scientific network, deputy lead for the Penta Training and Education Working group and a faculty member for Penta courses on paediatric HIV, congenital infection, hepatitis and TB. He leads or contributes to a number of national and international guidelines on infection in childhood and pregnancy. He is also secretary of the British Paediatric Allergy Infection and Immunity Group (BPAIIG).

Culture

Finn is training for a long cycle from Bristol to Paris, which sometimes takes her on cycles out of London, into the countryside.

Alasdair mentioned the New York Public Library, where he spent some time working in recently

Consult Notes

Consult Q

You are called by the NICU about an 18 day old baby born at 30+6 who developed feeding intolerance, respiratory distress, and temperature instability.

Key Points

Welcome to our second edition of “Curious Congenital Conundrums”!

This episode is part of a set of 4 (including 79, 80, 81, 82). If you missed the prior congenital series from the previous season, you can check out episodes 36, 37, 39, 41, 43 where we discussed the framework of SCORTCH (as opposed to TORCH) and 4 cases of CMV, syphilis, toxoplasma, and HSV in pregnancy and the congenital or neonatal setting.

Congenital enterovirus - Background / Epidemiology / Transmission

Infections in newborns may be acquired vertically before, during, or after delivery, horizontally from family members, or by nosocomial transmission in nurseries
Difficult to estimate the actual incidence of congenital enterovirus because enteroviral infections are common in the general population, have variable symptoms, and are asymptomatic in as many as 50% of the cases
Newborns presenting with serious enterovirus disease typically acquired the infection from a symptomatic mother in perinatal period
Up to 60% of mothers of infected infants reported a febrile illness during the last week of pregnancy
However infection may also be acquired via nosocomial transmission and spread through nurseries by caregivers engaged in mouth care, gavage feeding, and other activities requiring direct contact
So aspects of history that may support diagnosis of congenital enteroviral infection (like in our case) include:
- - Non-specific febrile illness in mother around delivery with rash
  - Subsequent illness in the sibling
  - Other things to consider: seasonality of enteroviruses, other environmental exposure (ie. exposure to other children), daycare, sick contacts
  - Need to also consider the current local epidemiology ie. any known outbreaks, increased circulation of enteroviruses
The group B coxsackievirus serotypes 2 to 5 and echovirus 11 have been more frequently associated with overwhelming systemic neonatal infections
Modlin JF. Perinatal echovirus infection: insights from a literature review of 61 cases of serious infection and 16 outbreaks in nurseries. Rev Infect Dis. 1986;8(6):918-926. doi:10.1093/clinids/8.6.918
Lake AM, Lauer BA, Clark JC, Wesenberg RL, McIntosh K. Enterovirus infections in neonates. J Pediatr. 1976;89(5):787-791. doi:10.1016/s0022-3476(76)80808-6
Kinney JS, McCray E, Kaplan JE, et al. Risk factors associated with echovirus 11′ infection in a hospital nursery. Pediatr Infect Dis. 1986;5(2):192-197. doi:10.1097/00006454-198603000-00006

Clinical Manifestations

Neonates are uniquely susceptible to enterovirus disease
Infections can be self-limited, mild/nonspecific, or fulminant and life-threatening → Need a high degree of suspicion for congenital enterovirus infection because symptoms can be non-specific
Systemic enterovirus disease in the newborn typically occurs as clinical syndrome of myocarditis or fulminant hepatitis
- - Neonatal myocarditis, often accompanied by encephalitis and hepatitis, is characteristically a manifestation of group B coxsackievirus infection
  - Fulminant hepatitis presenting with hypotension, profuse bleeding, jaundice, and multiple organ failure has been documented with multiple echovirus serotypes
A systematic review of 237 cases found that: 46.0% neonates had hepatitis or coagulopathy, 37.1% had myocarditis, 11.0% had meningoencephalitis, and 5.9% had other complications such as hemophagocytic lymphohistiocytosis and pulmonary hemorrhage. The highest mortality rate was seen in those with myocarditis. Coxsackievirus B infection was seen in 52.3% of cases. In 70.5% neonates, the age at the onset of symptoms was less than 7 days.
- - Zhang, Meng et al. “Clinical characteristics of severe neonatal enterovirus infection: a systematic review.” BMC pediatrics vol. 21,1 127. 15 Mar. 2021, doi:10.1186/s12887-021-02599-y
The outcome of neonatal infection is strongly influenced by presence or absence of passively acquired maternal neutralizing antibody >> so timing of maternal infection in relation to development of maternal IgG Ab and delivery of infant is critical factor in determining the outcome of neonatal enterovirus infection
- - Modlin JF, Polk BF, Horton P, Etkind P, Crane E, Spiliotes A. Perinatal echovirus infection: risk of transmission during a community outbreak. N Engl J Med. 1981;305(7):368-371. doi:10.1056/NEJM198108133050703
  - Berry PJ, Nagington J. Fatal infection with echovirus 11. Arch Dis Child. 1982;57(1):22-29.
Neurodevelopmental sequelae have been reported following severe infections with central nervous system involvement

Diagnosis & Evaluation

Many enterovirus infections in older children are diagnosed on clinical manifestations and are self-limited, but a lab diagnosis is warranted when the infection is more severe or has additional implications, such as CNS infection and neonatal infection
Virus can be detected in blood, cerebrospinal fluid, pericardial or respiratory fluid, urine, or tissue via RT-PCR, which is diagnostic of infection, rapid, sensitive, and widely available
- - Detection of enterovirus in respiratory secretions generally indicates acute infection although prolonged respiratory shedding is possible
  - Positive stool PCR is supportive as well (but in older children less definitive because could represent prolonged carriage from prior infection)
    - - In countries where oral poliovirus vaccine is used, this may confound positive results of PCR assays
Alasdair shared how he was taught that enterovirus moves between compartments during the stages of infection → so you need to look for enterovirus everywhere. If you don’t find it in one site like blood, it may be found in other sites. Submission of specimens from multiple sites for PCR testing may enhance the likelihood of detection
- - Rotbart HA, McCracken GH Jr, Whitley RJ, et al. Clinical significance of enteroviruses in serious summer febrile illnesses of children. Pediatr Infect Dis J. 1999;18(10):869-874. doi:10.1097/00006454-199910000-00007
  - Rotbart HA, Ahmed A, Hickey S, et al. Diagnosis of enterovirus infection by polymerase chain reaction of multiple specimen types. Pediatr Infect Dis J. 1997;16(4):409-411. doi:10.1097/00006454-199704000-00014
Most PCR assays will not identify the serotype (generally limited to identifying viral RNA at species level)
Cell culture based methods sent to reference labs may be required when typing of the isolate is important
- - This method is expensive and labor intensive >> so reserved for when typing of isolate is important for clinical/epidemiology or research purposes
Serology is not useful for diagnosis of acute infection

Management

As Alasdair discussed, the management is a bit of a grey area because the evidence base for what to do in severe enteroviral infection in a child this age (whether congenital or postnatally acquired infection) is not really there
Supportive care is the cornerstone of treatment
IVIG is not routinely used for enteroviral infections but is reasonable to consider on individual patient basis in those with severe infections
- - The evidence for neonatal enterovirus infection has been mixed
  - Case reports have described favorable outcomes: Johnston JM, Overall JC Jr. Intravenous immunoglobulin in disseminated neonatal echovirus 11 infection. Pediatr Infect Dis J. 1989;8(4):254-256.
  - This retrospective study in 67 cases of confirmed infection noted IVIG was independently associated with survival: Yen MH, Huang YC, Chen MC, et al. Effect of intravenous immunoglobulin for neonates with severe enteroviral infections with emphasis on the timing of administration. J Clin Virol. 2015;64:92-96. doi:10.1016/j.jcv.2015.01.013
  - But an RCT of IVIG 750 mg/kg found neither clinical benefit nor reduction in viremia (16 infants with enterovirus infection): Abzug MJ, Keyserling HL, Lee ML, Levin MJ, Rotbart HA. Neonatal enterovirus infection: virology, serology, and effects of intravenous immune globulin. Clin Infect Dis. 1995;20(5):1201-1206. doi:10.1093/clinids/20.5.1201
Antiviral therapy can also be considered for potential life threatening exceptions such as fulminant neonatal infection (other possible examples in older children would include severe myocarditis, chronic infection in B-cell immunodeficient patients, disseminated infections in children with hematologic malignancies)
- - These therapeutic options are limited and should be discussed in consultation with expert
  - These antivirals often have limited clinical availability as well, and in the USA, there are none that the FDA has approved (which would require exploration under IND application)
  - Pocapavir: (V-073)
    - - Oral capsid inhibitor, under development to treat chronic enterovirus infections
      - Reduced duration of poliovirus vaccine virus excretion in placebo controlled randomized trial of adults given OPV challenge: Collett MS, Hincks JR, Benschop K, et al. Antiviral Activity of Pocapavir in a Randomized, Blinded, Placebo-Controlled Human Oral Poliovirus Vaccine Challenge Model. J Infect Dis. 2017;215(3):335-343. doi:10.1093/infdis/jiw542
        Notes: resistant virus can develop
  - Pleconaril:
    - - Oral capsid inhibitor with favorable PK profile, has been tested clinically against a spectrum of enterovirus and rhinovirus infections, including serious enterovirus infections
      - Not currently available for systemic administration
      - This trial of 61 neonates with suspected enteroviral disease received 7d of pleconaril vs placebo with a trend toward more rapid viral clearance and lower overall mortality in those who received pleconaril: Abzug MJ, Michaels MG, Wald E, et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis. J Pediatric Infect Dis Soc. 2016;5(1):53-62. doi:10.1093/jpids/piv015
        Notes: early termination due to slow enrollment; concomitant IVIg use
      - Enteroviral meningitis, patients had modest benefit in headache duration: Desmond RA, Accortt NA, Talley L, Villano SA, Soong SJ, Whitley RJ. Enteroviral meningitis: natural history and outcome of pleconaril therapy. Antimicrob Agents Chemother. 2006;50(7):2409-2414. doi:10.1128/AAC.00227-06
  - There are other drugs under development or study, including repurposed antivirals (eg favipiravir) or medications with potential antiviral properties (eg SSRIs like fluoxetine, fluvoxamine)
Alasdair also discussed how other immunomodulatory agents may be discussed by the multidisciplinary team in certain severe cases, but there is no clear evidence of this / would be experimental

Infection prevention and control

Ensure diligent hand washing and cough etiquette
In hospitalized patients, standard precautions are indicated >> but in diapered children, should use contact precautions for duration of illness and to control institutional outbreaks
In outbreak settings, contact and droplet precautions are often used for suspect cases

Autoimmune neutropaenia of infancy

The patient example in the episode developed persistent neutropenia and was found to have granulocyte immunofluorescence test is positive for HNA1a specific granulocyte antibodies, suggesting autoimmune neutropaenia of infancy
There is a type of neutropenia that is noted in an otherwise normal infant, termed neonatal isoimmune (alloimmune) neutropenia
- - This can occur due to transplacental passage of IgG antibodies to neutrophil-specific antigen inherited from the father (although rarely can arise from autoimmune neutropenia in the mother; similar to pathogenesis Rh hemolytic disease)
  - These patients typically do well without major issues, with resolution of neutropenia within 3-4 months
Autoimmune neutropaenia of infancy (AIN) is caused by granulocyte-specific antibodies and has been associated with a variety of underlying diseases, including certain viral infections early in infancy
- - Parvovirus and HIV infection have been specifically implicated in the development of autoantibodies to neutrophils
  - A case series of two infants with congenital CMV and subsequent AIN has also been described: Penner J, Chan CS, Burns JE, Ali S, Lyall H. Congenital Cytomegalovirus and Autoimmune Neutropenia: Cause or Coincidence?. Pediatr Infect Dis J. 2020;39(4):336-338. doi:10.1097/INF.0000000000002583
  - Other viral agents have been linked, particularly viruses of the Herpesviridae family
  - Other non-infectious diseases with associations include: collagen vascular disease, primary abnormalities of B/T/NK cells (eg autoimmune lymphoproliferative syndrome, ALPS), deficiency of regulatory T cells, immune thrombocytopenia, autoimmune hemolytic anemia

In most cases, AIN is not associated with other disease and is referred to as chronic benign neutropenia
- - Typically occurs in infants between 5-15 mo of age (but can extend into adulthood)
Antineutrophil antibodies are detected in 98-100% of patients with AIN
- - HNA-1a and HNA-1b are the most common antineutrophil autoantibodies found in AIN
  - The origin of these autoantibodies are unknown, but molecular mimicry as a result of exposure to viral or microbial antigens has been hypothesized
References on AIN:

Enteroviruses are associated with chronic inflammation with a known propensity to induce autoimmunity via induction of pro-inflammatory cytokines of the TH1 and IL10 pathways, altering their role in both cellular and humoral immune responses but a lot remains unknown
Overall, more research is needed to explore the interaction between viral congenital infections and the immune system

Episode Art & Infographics

Infographics

Find all the Febrile infographics here!

Goal

Listeners will be able to understand the clinical presentation and evaluation of congenital enterovirus infection

Learning Objectives

After listening to this episode, listeners will be able to:

Discuss the epidemiology of enterovirus
Describe the diagnosis and characteristic features of congenital enterovirus infection
Recognize the limited management options for congenital enterovirus infection
Define autoimmune neutropenia of infancy

Disclosures

Our guests (Finn Ryan, Alasdair Bamford) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Ryan, F., Bamford, A., Dong, S. “#80: Curious Congenital Conundrums – Viral Rival”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/000f67f6-101b-4c43-96f9-423f29c27c55

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