Bianchi Simona

De Vito Rita

Di Camillo Chiara

Gonfiantini Michaela Veronika

Valentini Diletta

Villani A

Vittucci Anna Chiara

English

CASE REPORT Open AccessFatal varicella pneumonia in anunvaccinated child with DownSyndrome: a case reportDiletta Valentini1*, Simona Bianchi1, Chiara Di Camillo1, Anna Chiara Vittucci1, Michaela Veronika Gonfiantini1,Rita De Vito2 and Alberto Villani1AbstractBackground: Varicella is an acute infectious disease common during childhood. It has mostly an uncomplicatedcourse in early childhood. Neverthless, it may result in severe complications, especially in particular age groups andclinical conditions. Down Syndrome represents a risk factor for developing complications, because of the frequentcomorbidities and their immunodeficiency.Case presentation: A 2-year-old white Caucasian female affected by Down Syndrome was referred to our hospitalfor cardiac arrest in course of varicella disease. After cardiopulmonary resuscitation and stabilization, her clinicalconditions didn’t improve and she developed a massive pulmonary hemorrage, which led her to exitus.Conclusions: Mortality due to varicella infection is rare, but it is more common in subjects with immune deficit orchronic pathologies, and in particular age-groups. The importance of the vaccine for preventable infectious diseasesis stressed in this paper, in which we present a case of death in an unvaccinated cardiopathic child with DownSyndrome affected by varicella.Keywords: Down Syndrome, Immunodeficiency, Varicella, Pneumonia, Vaccination, Case reportBackgroundVaricella is an acute, exanthematous, highly infectious dis-ease, that most commonly occurs in childhood. Varicellanormally has a benign course, but can occasionally de-velop into a more serious illness, especially in adults,immunodeficient children, pregnant women, newbornbabies [1]. A lethal outcome is very rare, with a mortal-ity rate fluctuating between 0.29 and 0.46 deaths per 1million. The introduction of the vaccine in 1995 hassubstantially decreased varicella incidence, hospitaliza-tions, and deaths [2].The most common complications of varicella arebacterial skin infection, sepsis, pneumonia, and centralnervous system events such as cerebellar ataxia andencephalitis [3, 4].Case presentationA 2-years-old white Caucasian female affected by DownSyndrome (DS) and surgically corrected at 3 months ofage for a subaortic intraventricular defect (IVD), with ahistory of 2 episodes of pneumonia, was admitted inthe emergency room of our hospital due to a cardiac ar-rest during her varicella illness. She had never beenvaccinated up to the moment, that’s why she contractedthe disease from her sister. The night before her admis-sion to the hospital, she began to manifest episodes ofhypotonia associated to periods of crying. At 4 o’clockshe began to show signs of a generalized hypotonia andshe was taken to our hospital by her parents, where shearrived in cardiac arrest. After Cardio-Pulmonary Re-suscitation (CPR-PALS) her spontaneous breathing wasrestored. The clinical course was characterized bycomplete areflexia, with bilateral mydriasis. Breathingpattern was characterized by ARDS that required highfrequency mechanical ventilation and Nitric Oxide withtransient improvement.* Correspondence: diletta.valentini@opbg.net1Pediatric and Infectious Disease Unit, Bambino Gesù Children’s Hospital,IRCCS, Rome, ItalyFull list of author information is available at the end of the article© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Valentini et al. Italian Journal of Pediatrics  (2016) 42:99 DOI 10.1186/s13052-016-0312-1We proceeded to perform a chest X-ray (CXR), whichrevealed multiple foci of parenchymal spread to bothlungs and pleural effusion obliterating share of thebreast-phrenic cost (Fig. 1). An abdominal ultrasoundshowed the presence of abdominal effusion in all quad-rants and laboratory tests revealed the presence of IgMantibodies against varicella, positive PCR for varicellaantigen, absence of bacterial infections (coltures of bloodand urine), prolonged PT and PTT, and altered D-Dimer.Tests for immunological functions were performed(Table 1).The next day, the respiratory condition didn’t improveand a new CXR showed an impairment of the spread,and a massive pulmonary hemorrhage. In the absence ofrecovery of the main indicators of organ perfusion, shewas declared dead.At macroscopic examination the lungs were heavy,firm and plum-colored, with diffuse areas of hemorrhageand necrosis.Histologically there are interstitial pneumonitis, diffusenecrosis and hemorrhage in the pulmonary parenchyma(Fig. 2).ConclusionsThe estimated global burden of disease-specific mortalitycaused by varicella is considerably lower than that due toother major infectious diseases such as measles, pertussis,rotavirus, or invasive pneumococcal disease. Based onconservative estimates, the global annual varicella diseaseburden reports 4.2 million severe complications leading tohospitalization and 4200 deaths [5].The prevalence of immunocompromising conditionsincluding HIV infection and the kind of treatmentavailable, are factors which influence the course of thedisease. In healthy children, varicella is usually self-limiting and benign [6].Groups at higher risk for severe complications are: ne-onates, infants, pregnant women, adults, and immuno-compromised patients.The type of varicella complications depends on the pa-tient’s age. A study of Gowin et al. demonstrates that theaverage age of varicella-complications in hospitalizedchildren is 3.12 years [7, 8]. The youngest children hadpneumonia, and the oldest meningitis/meningoencephalitis[9, 10].Older children considered to be more susceptible toantibody-mediated inflammatory reactions, whereas youn-ger, less immunocompetent patients are more frequentlyaffected by bacterial suprainfections of the skin or of therespiratory tract [11, 12].Respiratory tract infections were present in youngerchildren, and usually developed at the beginning of thevaricella infection [7]. The high frequency of respiratorytract complications reflects the biology of the virus. Thevirus enters the host through the respiratory tract andthen spreads in the bloodstream. A cytopathic effect ofFig. 1 Chest X-Ray: multiple foci of parenchymal spread to both lungs and pleural effusion obliterating share of the breast-phrenic costValentini et al. Italian Journal of Pediatrics  (2016) 42:99 Page 2 of 4the varicella virus on the alveolar epithelium causespneumonia. Desquamated alveolar cells contribute toreduce gas exchange.Hematological complications are observed in 1–2% ofchildren with varicella. Patients usually remain asymptom-atic. Like many other thrombocytopenias and anemiasduring viral infections, those in patients with varicella aretransient and require no treatment. Laboratory tests arenot performed routinely in patients with varicella [13].Our case suffered from acute respiratory distress syn-drome (ARDS) caused by varicella, and associated tohematological disorders that provoked the developmentof pulmonary hemorrhage, which caused death.Children who are diagnosed with Down syndrome andwho have comorbidities such as immunodeficiency or car-diopathy have high rates of viral and bacterial infectionssuch as influenza and pneumococcal infections [14]. Themost common symptoms reported in children with DSare infections of the respiratory tract suggesting a B-celldefect [15]. Diseases related to T-cell deficiency, such asinfection with intra-cellular microorganism, fungi and op-portunistic pathogens are rare [16].Varicella is one of the most infective disease that affectsthe pediatric population.Guidelines stress the importance of an anti-varicellavaccination for all children older than 12 months aswell as children with DS [17]. The only contraindica-tion of the vaccine is severe immunodeficiency of the Tcells [6]. Despite the fact that most children hospital-ized with varicella complications were immunologicallyhealthy, risks are superior in subjects with chronicconditions [6, 18].Children with DS have a higher risk of being hospital-ized for viral respiractory tract infections, even in the ab-sence of coexisting risk factors [19], and the mortality ratein severe ill DS children admitted for medical reasons ishigh and is predominantly associated with respiratoryconditions [20]. As the burden of preventable infections inchildren diagnosed with chronic diseases is high in termsTable 1 Blood investigations performed at the emergencyroom accessInvestigation Value Reference valueWhite bllod cells 15.65 (*103/uL) 5.5–15Red blood cells 4.03 (*106/*uL) 3.6–5Hemoglobin 9 (g/dL) 10.5–15.5Platelets 131 (103/uL) 150–450PTT-s 50.5 (seconds) 25–34PTT-r 1.73 (seconds) 0.85–1.15Trombin Time 27.6 (seconds) 16–22Antitrombine III 34 (%) 75–120Fibrinogen Dimeri 6.7 (microg/mL) <0.5LDH 4150 (UI/L) 230–470CPK 3595 (UI/L) 32–211CD3-pan T 56.4 (%) 58–75CD4 T Helper 16.8 (%) 29–47CD8 T Suppressor/Cytotoxic 39.7 (%) 17–33CD19 Pan B 36 (%) 14–30CD16 + CD56+ 6.7 (%) 4–17VZV PCR positive NegativeVZV IgG negative –VZV IgM positive –Fig. 2 Histological image that showed interstitial pneumonitis and diffuse necrosis and hemorrhage in the pulmonary parenchymaValentini et al. Italian Journal of Pediatrics  (2016) 42:99 Page 3 of 4of incidence and severity, it is essential to protect thesechildren with timely administration of vaccinations ac-cording to the current recommendations.Even among populations at risk, varicella vaccine is theless used. Although Italian Down children have the bestvaccination coverage among all patients with chronicdisease [21], it is clear that it is desirable to improvevaccination coverage among risk groups and also amongthe healthy population.Implemented interventions, with special reminders toparents and general practitioners, are necessary to promotetimely vaccination in DS children who are susceptible topreventable infections and prone to severe complications.This case underlines how varicella may lead to severe,potentially life-threatening complications in unvaccinatedchildren and adolescents, and may demonstrate too thebenefits of varicella vaccination.AbbreviationsARDS: Acute respiratory distress syndrome; CPR-PALS: Cardio-PulmonaryResuscitation; CXR: Chest X-ray; DS: Down SyndromeAknowledgementsNo aknowledgements.FundingDiletta Valentini, who wrote the first draft of the manuscript, wasn’t given byanyone any grant or other form of payment to produce the manuscript.Availability of data and materialsThe dataset supporting the conclusions of this article is available in theBambino Gesù Children Hospital repository.Authors’ contributionsDV wrote the manuscript. SB collected the clinical and laboratory data,and wrote the manuscript. CDC collected the bibliography. AV reviewedthe immunization schedule for Down Syndrome, in order to write thediscussion. MVG reviewed the clinical complications of varicella, in orderto write the discussion. RDV performed the pathological analysis. AV reviewedthe manuscript. All authors read and approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Consent for publicationWritten informed consent was obtained from the patient’s parents/legalguardians for publication of this case report and any accompanying images. Acopy of the written consent is available for the review by the Editor-in-Chief ofthis journal.Ethics approval and consent to participateNot applicable.Author details1Pediatric and Infectious Disease Unit, Bambino Gesù Children’s Hospital,IRCCS, Rome, Italy. 2Pathology Unit, Bambino Gesù Children’s Hospital, IRCCS,Rome, Italy.Received: 7 August 2016 Accepted: 11 November 2016References1. Kimberlin D, Brady MT, Jackson MA, Long SS. Red Book, 30th ed, AmericanAcademy of Pediatrics. 2015:846–60.2. Huong Q, Nguyen MPH, Aisha O. Decline in mortality due to varicella afterimplementation of varicella vaccination in the United States. N Engl J Med.2005;352:450–8.3. Losurdo G, Bertoluzzo L, Canale F, Timitilli A, Bondi E, Castagnola E,Giacchino R. Varicella and its complications as cause of hospitalization. InfezMed. 2005;13:229–34.4. Bozzola E, Bozzola M, Tozzi AE, Calcaterra V, Longo D, Kryzystofiak A, VillaniA. Acute cerebellitis in varicella: a ten years case series and systematicreview of the literature. It J Pediatr. 2014;40:57.5. Trucchi C, Gabutti G, Rota MC, Bella A. Burden of varicella in Italy, 2001–2010: analysis of data from multiple sources and assessment of universalvaccination impact in three pilot regions. J Med Microbiol. 2015;64:1387–94.6. World Health Organisation. Varicella and herpes zoster vaccines: WHOposition paper 2014;9:265–2887. Dubos F, Grandbastien B, Hue V, Martinot A. Epidemiology of hospitaladmissions for paediatric varicella infections: a one-year prospective surveyin the pre-vaccine era. Epidemiol Infect. 2007;135:131–8.8. Liese JG, Grote V, Rosenfeld E, Fischer R, Belohradsky BH, Kries RV. Theburden of varicella complications before the introduction of routinevaricella vaccination in Germany. Pediatr Infect Dis J. 2008;27:119–24.9. Gowin E, Wysocki J, Michalak M. Don’t forget how severe varicella canbe—complications of varicella in children in a defined Polish population. IntJ Infect Dis. 2013;17:e485–9.10. Bozzola E, Tozzi AE, Bozzola M, Krzysztofiak A, Valentini D, Grandin A, VillaniA. Neurological complications of varicella in childhood: case series and asystematic review of the literature. Vaccine. 2012;30:5785–90.11. Hervas D, Henales V, Yeste S, Figuerola J, Hervas J. How frequent isvaricella associated pneumonia in children? Eur J Clin Microbiol InfectDis. 2011;30:435–7.12. Patel RA, Binns HJ, Shulman ST. Reduction in pediatric hospitalizations forvaricella-related invasive group A streptococcal infections in the varicellavaccine era. Pediatrics. 2004;144:68–74.13. Bozzola E, Quondamcarlo A, Krzysztofiak A, Pandolfi E, Lancella L, Tozzi AE.Haematological complications in otherwise healthy children hospitalized forvaricella. Vaccine. 2011;29:1534–7.14. American Academy of Pediatrics. Committee on Infectious Diseases. Policystatement: recommendation for the prevention of pneumococcal infections,including the use of pneumococcal conjugate vaccine (Prevenar),pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics.2000;106:362–6.15. Carsetti R, Valentini D, Marcellini V, Scarsella M, Marasco E, Giustini F, BartuliA, Villani A, Ugazio AG. Reduced numbers of switched memory B cells withhigh terminal differentiation potential in Down syndrome. Eur J Immunol.2015;45:903–14.16. Verstegen RH, Kusters MA, Gemen EF, de Vries E. Down Syndrome B-Lymphocyte subpopulations, intrinsic defect or decresead T-lymphocytehelp. Pediatr Res. 2010;67:563–9.17. Gallo G, Mel R, Rota MC. Guide to contraindications to vaccination. 2009, v,92 p. Rapporti ISTISAN 09/13 (in Italian).18. Oxman MN, Schmader KE. Editorial commentary: zoster vaccine inimmunocompromised patients: time to reconsider currentrecommendations. Clin Infect Dis. 2014;59:920–2.19. Zachariah P, Ruttenber M, Simões EA. Down syndrome and hospitalizationsdue to respiratory syncytial virus: a population-based study. J Pediatr.2012;160:827–31.20. Joffre C, Lesage F, Bustarret O, Hubert P, Oualha M. Children with Downsyndrome: Clinical course and mortality-associated factors in a French medicalpaediatric intensive care unit. J Paediatr Child Health. 2016;52:595–9.21. Pandolfi E, Carlonia E, Marinoa MG, Ciofi degli Atti ML, Gesualdo F, RomanoM, et al. Immunization coverage and timeliness of vaccination in Italianchildren with chronic diseases. Vaccine. 2012;30:5172–8.Valentini et al. Italian Journal of Pediatrics  (2016) 42:99 Page 4 of 4

Fatal varicella pneumonia in an unvaccinated child with Down Syndrome: a case report

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Fatal varicella pneumonia in an unvaccinated child with Down Syndrome: a case report

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