Clinical letterTo date, severe cases of vaccine-related rotavirus infection have only been reported in infants with severe combined immunodeficiency after immunization. We describe the first case of vaccine-related rotavirus gastroenteritis in an infant with intestinal lymphangiectasia.S

Cabrerizo, Maria

Fernandez Garcia, Maria Dolores

Hidalgo Montes, Inmaculada

Martinez Ojinaga, Eva

Méndez Echevarría, Ana María

Pastrian, Laura G.

Rodrieguez Pena, Rebeca

Rosal Rabes,  Teresa del

Ruiz Carrascoso, Guillermo

Pediatric Allergy and Immunology

English

Hidalgo-Montes, Inmaculada

Mendez-Echevarria, Ana

Rodrieguez-Pena, Rebeca

Ruiz-Carrascoso, Guillermo

Martinez-Ojinaga, Eva

Del Rosal, Teresa

Pastrian, Laura G

Fernandez-Garcia, Maria Dolores

REPISALUD

Pediatr Allergy Immunol. 2022;33:e13834.	 	 	 | 1 of 4https://doi.org/10.1111/pai.13834wileyonlinelibrary.com/journal/paiReceived:	7	April	2022  | Revised:	4	July	2022  | Accepted:	7	July	2022DOI: 10.1111/pai.13834  C L I N I C A L  L E T T E RSevere vaccine- acquired rotavirus infection in an infant with primary intestinal lymphangiectasiaTo the Editor:Rotarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium) is a mono-valent oral live- attenuated vaccine derived from human rotavirus G1P[8].1 It is specifically contraindicated for infants diagnosed with severe combined immune deficiency (SCID), with a history of intus-susception or a history of uncorrected congenital malformation of the gastrointestinal tract.1 However, in the absence of newborn screen-ing for SCID, most undiagnosed infants with contraindications stated above are at increased risk of developing vaccine- acquired rotavirus infection. Several cases of severe gastroenteritis have been reported in infants with SCID when Rotarix was administered prior to diagnos-tic confirmation,2 but no data are available contraindicating it for other immunocompromised hosts with conditions different from SCID.We describe the first case of a previously asymptomatic infant who developed a severe vaccine- acquired rotavirus infection after receiving the first Rotarix dose, associating lymphopenia and hypo-albuminemia. This ultimately led to the diagnosis of primary intesti-nal lymphangiectasia (PIL), being SCID ruled out. The patient was a two- month- old full- term male infant, the first child of nonconsan-guineous parents. The child had a good developmental curve and did not attend daycare. Twenty- four hours after Rotarix administration, he developed diarrhea that progressively worsened and resulted in weight loss and in eyelid and scrotal edemas. Hospital admission was required	7 days	after	vaccine	administration.	No	growth	retardation	has been observed until he was vaccinated. He was transferred to our	hospital	13 days	after	 immunization,	requiring	24 h	of	pediatric	intensive care due to severe dehydration and significant electrolyte disturbances.When he was first admitted to our hospital, he presented with severe lymphopenia (230/mm3),	 hypoalbuminemia	 (1.2 mg/dL),	 and	elevated	 faecal	 alpha-	1-	antitrypsin	 levels	 (7.71 U/g)	with	a profound decrease in IgG and IgA levels. The patient was placed on	 cotrimoxazole	 prophylaxis	 and	 gammaglobulin	 replacement	therapy (Figure 1, Table 1). A complete immunological study was performed that showed normal results (Table 1). The patient's DNA	was	screened	for	genetic	variants	of	genes	related	to	primary	immunodeficiencies (PIDs) using a next- generation sequencing- customized	 panel	 including	 479	 genes	 without	 pathogenic	 find-ings. A histological study of the intestinal biopsy showed lymphatic dilations suggestive of lymphangiectasia. Several studies were performed to rule out secondary causes of lymphangiectasia (car-diac evaluation, ultrasound, and intestinal barium tests). A multi-plex PCR- based detection of 18 enteropathogens performed on stool samples [Allplex™ Gastrointestinal Panel Assays (Seegene, Seoul,	South	Korea)]	only	detected	rotavirus	on	days	22,	29,	and	37	after vaccine administration (Figure 1). PCR testing for herpesvirus in blood and intestinal biopsy were negative. The patient required prolonged	parenteral	nutrition,	octreotide	therapy	(4 weeks),	peri-odic	 infusions	of	albumin,	 and	nitazoxanide	 therapy	 (3 days).	The	patient was required to fast for several days and received paren-teral nutrition for several weeks, being re- fed progressively with a strict low- fat diet supplemented with fat in the form of MCT. The patient showed progressive improvement in digestive tolerance, which allowed the withdrawal of parenteral nutrition (Figure 1). The analytical parameters of lymphatic loss subsequently showed a	 clear	 trend	 towards	 improvement	 and	 normalized	 14	 months	after the infection (Figure 1, Table 1). However, the patient needs to remain on this strict low- fat diet with MCTs in order to maintain an optimal serum albumin and lymphocyte count.Genome segments coding for VP4, VP6, and VP7 structural pro-teins were amplified by PCR and sequenced from the stool sample obtained	 22 days	 after	 Rotarix	 administration	 (lot	 AROLC991AB).	Nucleotide	and	amino	acid	 sequences	were	compared	 to	 those	of	Rotarix	in	the	GenBank	database.	Lot	AROLC991AB	yielded	an	iden-tical sequence to the Rotarix sequence for each of the three genes tested (VP4, VP6, and VP7) with the exception of three nucleotide and three amino acid substitutions (Table S1). Genome sequences from	a	stool	specimen	obtained	7 days	apart	were	 identical	 to	 the	first sample.We describe the first case of severe vaccine- acquired rotavirus disease in an infant vaccinated with Rotarix and diagnosed with PIL. Although administering this vaccine to patients with gastrointesti-nal malformations is contraindicated, PIL is exceptionally diagnosed before the age of two months3. Thus not administering Rotarix to these patients is an unlikely scenario. Patients with PIL presented with a predominant loss of CD4+ T cells4. Although the number of naïve CD4+ T cells is decreased, memory CD4+ cells are preserved and could have a role in preventing infections4.	Naïve	CD4+ cells are the predominant subset in infants, therefore they might be more susceptible to opportunistic and viral infections.This is an open access article under the terms of the Creative	Commons	Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.© 2022 The Authors. Pediatric Allergy and Immunology	published	by	European	Academy	of	Allergy	and	Clinical	Immunology	and	John	Wiley	&	Sons	Ltd.2 of 4  |     CABRERIZO et al.F I G U R E  1 Lymphocyte	count	(A),	IgG	titers,	and	serum	albumin	(B)	in	our	patient	and	their	relationship	with	the	clinical	timeline	(C) 13993038, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13834 by Readcube (Labtiva Inc.), Wiley Online Library on [09/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License    |  3 of 4CABRERIZO et al.Prasad et al.5 recently published the clinical profile of 28 chil-dren diagnosed with PIL and observed that 10% of these children presenting with recurrent infections. Other authors have also re-ported severe and/or opportunistic infections, such as cryptococcal and	pneumococcal	meningitis,	recurrent	warts,	varicella	zoster,	and	bacterial sepsis, with a number of these patients dying due to the infection.6Rotarix vaccine- derived G1[P8] strains have been globally described	 in	 infants	 around	 the	 time	 of	 their	 routine	 immuniza-tion.7,8 This shedding has not been associated with an increase in gastroenteritis- like symptoms.9 Our patient's stool samples (at 22, 29,	and	37 days	postvaccination)	were	persistently	positive	 for	 ro-tavirus by quantitative reverse- transcription PCR, coinciding with clinical worsening, and leading to the diagnosis of PIL.Prolonged shedding of vaccine strain rotavirus is also reported in infants with SCID, who usually require successful immune recon-stitution to clear the infection.2,10,11 The development of severe gastroenteritis after rotavirus vaccination could be the trigger that leads to a diagnosis of their underlying disease in infants with SCID2 as we have observed in our case. Many of these children will require hospital admission.2	 In	our	patient,	nitazoxanide	was	prescribed	as	this drug is able to reduce the duration of rotavirus disease in severe hospitalized	pediatric	patients.12The	 G1[P8]	 strain	 detected	 in	 our	 patient	 was	 analyzed.	Nucleotide	 sequencing	and	phylogenetic	 analysis	of	 the	VP4,	VP6,	and VP7 coding genes revealed very high nucleotide and amino acid identity rates between the study and the Rotarix strains, supported by high bootstrap values in the phylogenetic analysis (Figure S1). The high similarity to the Rotarix vaccine strain and the failure to detect other common enteric pathogens reassure the likelihood of infection caused by the vaccine- derived strain. Mutations F170L in VP4 and M202T in VP7 had been documented earlier for all described cases of Rotarix vaccine- derived strains and have caused acute gastroenteritis in infants with SCID (Table S2). It is plausible that the vaccine strain could have regained a pathogenic phenotype through these newly acquired mutations. Changes could be due to genetic drift occurring since the administration of the vaccine or because of the in vivo selec-tion of minor variants already present in the vaccine13.Our case report highlights the risk of this vaccine in patients with PIL. The presence of other causes of lymphopenia different from SCID should be also considered in infants with severe gastrointesti-nal symptoms after rotavirus vaccination.Key MessageTo date, severe cases of vaccine- related rotavirus infection have only been reported in infants with severe combined immunodeficiency	 after	 immunization.	 We	 describe	 the	first case of vaccine- related rotavirus gastroenteritis in an infant with intestinal lymphangiectasia.2.5 Months of age (14 days after vaccination) 7 Months 11 MonthsLymphocyte count 620/μL 1090/μL 2890/μLLymphocyte subsets (% of lymph CD45+)T CD3+ 28% (173/μL) 67 (730/μL) 70(2023/μL)T CD4+ 14% (86/μL) 42(457/μL) 44(1271/μL)T CD8+ 7% (43/μL) 20 (218/μL) 20 (578/μL)B	CD19+ 37% (230/μL) 23 (250/μL) 19	(549/μL)NK	CD16 + 56+ 32%	(198/μL) 7 (76/μL) 9	(260/μL)CD4 subsets (% of CD4):CD4 + CD31 + CD45RA+ (RTE)41% 68% 74%CD4 + CD127low	CD25+ (Treg)14% 7% 8%Proliferation test ConA; PHA; PWM; OKT3Normal	proliferation Normal	proliferationIgG <70 mg/dL 599 mg/dL* 354 mg/dLIgA <7 mg/dL <7 mg/dL <7 mg/dLIgM 24 mg/dL 33 mg/dL 31 mg/dLTRECs (copies/punch) 50 (normal>8) - - - - - - - - Note:	*Trough	levels	prior	to	immunoglobulin	replacement	therapy.Abbreviatioins:	ConA,	concanavalin	A;	NK,	natural	killer	cell;	PHA,	phytohemagglutinin;	PWM.	pokeweed- mitogen; RTEm, recent thymic emigrant; TRECs, T- cell receptor excision circles; Tregs, T regulatory cells.TA B L E  1 Immunological	studies	of	the	patient at diagnosis and during his clinical follow- up 13993038, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13834 by Readcube (Labtiva Inc.), Wiley Online Library on [09/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License4 of 4  |     CABRERIZO et al.ACKNOWLEDG MENTSWe	would	like	to	thank	Luis	Allende	at	Hospital	Universitario	12	de	Octubre for the quantification of TRECs; María Bravo Garcia- Morato at	La	Paz	University	Hospital	for	the	genetic	analysis	of	PID	genes	for	their contribution to the management and diagnosis of the patient.KE Y WORDSattenuated vaccine, intestinal lymphangiectasis, rotavirusCONFLIC T OF INTERE S TThe other authors have no example conflicts of interest to disclose.PEER RE VIE WThe peer review history for this article is available at https://publo ns.com/publo n/10.1111/pai.13834.Maria	Cabrerizo1,2Inmaculada Hidalgo- Montes3Ana	Mendez-	Echevarria4,5,6Rebeca	Rodrieguez-	Pena7,8Guillermo	Ruiz-	Carrascoso9Eva	Martinez-	Ojinaga3Teresa del Rosal4,5,8Laura G. Pastrian10Maria	Dolores	Fernandez-	Garcia11Enterovirus and Viral Gastroenteritis Unit, National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain2CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain3Department of Pediatric Gastroenterology, University Hospital La Paz, Madrid, Spain4Pediatric Infectious and Tropical Diseases Department, La Paz University Hospital, Madrid, Spain5Translational Research Network in Pediatric Infectious Diseases (RITIP), Madrid, Spain6CIBERINFEC (CB21/13/00049), Instituto de Salud Carlos III, Madrid, Spain7Immunology Department, Hospital Universitario La Paz- IdiPAZ, Madrid, Spain8Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III9Department of Clinical Microbiology, Hospital Universitario La Paz, Madrid, Spain10Department of Pathology, Hospital Universitario La Paz, Madrid, SpainCorrespondenceAna	Méndez-	Echevarría,	Pediatric	Infectious	and	Tropical	Diseases	Department,	La	Paz	University	Hospital,	Paseo	de	la Castellana 261, 28046, Madrid, Spain.Email: ana.mendez@uam.esMaria	Cabrerizo	and	Inmaculada	Hidalgo-	Montes	equally	contributed. ORCIDAna Mendez- Echevarria  https://orcid.org/0000-0002-7455-9080 R E FE R E N C E S 1. European Medicine Agency. Rotarix summary of product charac-teristics. https://www.ema.europa.eu/docum ents/produ ct- infor matio n/rotar ix- epar- produ ct- infor mation_en.pdf.	 2.	 Bakare	N,	Menschik	D,	Tiernan	R,	Hua	W,	Martin	D.	Severe	com-bined immunodeficiency (SCID) and rotavirus vaccination: reports to the vaccine adverse events reporting system (VAERS). Vaccine. 2010;28:6609-	6612.	 3.	 Lopez	RN,	Day	AS.	Primary	intestinal	lymphangiectasia	in	children:	a review. J Paediatr Child Health.	2020;56:1719-	1723.	 4.	 Lee	SJ,	Song	HJ,	Boo	SJ,	Na	SY,	Kim	HU,	Hyun	CL.	Primary	intesti-nal	lymphangiectasia	with	generalized	warts.	World J Gastroenterol. 2015;21:8467- 8472.	 5.	 Prasad	D,	Srivastava	A,	Tambe	A,	Yachha	SK,	Sen	SM,	Poddar	U.	Clinical profile, response to therapy, and outcome of children with primary intestinal lymphangiectasia. Dig Dis.	2019;37:458-	466.	 6.	 Dierselhuis	MP,	Boelens	JJ,	Versteegh	FGA,	Weemaes	C,	Wulffraat	NM.	 Recurrent	 and	 opportunistic	 infections	 in	 children	with	 pri-mary intestinal lymphangiectasia. J Pediatr Gastroenterol Nutr. 2007;44:382- 385. 7. Kaneko M, Takanashi S, Thongprachum A, et al. Identification of vaccine- derived rotavirus strains in children with acute gastro-enteritis	in	Japan,	2012-	2015.	PLoS ONE.	2017;12(9):e0184067.	 8.	 Hungerford	 D,	 Allen	 DJ,	 Nawaz	 S,	 et	 al.	 Impact	 of	 rotavirus	vaccination on rotavirus genotype distribution and diver-sity in England, September 2006 to august 2016. Euro Surveill. 2019;24(6):1700774.	 9.	 Anderson	EJ.	Rotavirus	vaccines:	viral	shedding	and	risk	of	trans-mission. Lancet Infect Dis.	2008;8:642-	649.	10.	 Gower	CM,	Dunning	J,	Nawaz	S,	Allen	D,	Ramsay	ME,	Ladhani	S.	Vaccine- derived rotavirus strains in infants in England. Arch Dis Child. 2020;105:553- 557.	11.	 Tanita	K,	Kawamura	Y,	Miura	H,	et	al.	Case	report:	rotavirus	vac-cination	 and	 severe	 combined	 immunodeficiency	 in	 Japan.	 Front Immunol. 2022;13. doi:10.3389/fimmu.2022.786375	12.	 Rossignol	 JF,	 Abu-	Zekry	 M,	 Hussein	 A,	 Santoro	 MG.	 Effect	of	 nitazoxanide	 for	 treatment	 of	 severe	 rotavirus	 diarrhoea:	randomised double- blind placebo- controlled trial. Lancet. 2006;368:124-	129.	13.	 Zeller	M,	 Patton	 JT,	Heylen	 E,	 et	 al.	Genetic	 analyses	 reveal	 dif-ferences in the VP7 and VP4 antigenic epitopes between human rotaviruses circulating in Belgium and rotaviruses in rotarix and RotaTeq. J Clin Microbiol.	2012;50:966-	976.SUPPORTING INFORMATIONAdditional supporting information can be found online in the Supporting Information section at the end of this article.Editor: Fabio Candotti 13993038, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13834 by Readcube (Labtiva Inc.), Wiley Online Library on [09/05/2023]. 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Severe vaccine-acquired rotavirus infection in an infant with primary intestinal lymphangiectasia

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Severe vaccine-acquired rotavirus infection in an infant with primary intestinal lymphangiectasia

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