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Adverse Events of the BCG (Bacillus Calmette–Guérin) and Rotavirus Vaccines in a Young Infant with Inborn Error of Immunity

Adverse Events of the BCG (Bacillus Calmette–Guérin) and Rotavirus Vaccines in a Young Infant... Hindawi Case Reports in Immunology Volume 2020, Article ID 8857152, 4 pages https://doi.org/10.1155/2020/8857152 Case Report Adverse Events of the BCG (Bacillus Calmette–Guerin) and Rotavirus Vaccines in a Young Infant with Inborn Error of Immunity 1 2 2 Suleiman Al-Hammadi , Najla S. Alkuwaiti, Ghassan A. Ghatasheh, 2 2 3 Huda Al Dhanhani, Hiba M. Shendi, Abdulghani S. Elomami, 1 1 Farida Almarzooqi , and Abdul-Kader Souid Department of Pediatrics, College of Medicine and Health Sciences, UAE University, Abu Dhabi, UAE Department of Pediatrics, Tawam Hospital, Alain, Abu Dhabi, UAE Department of Pathology, Tawam Hospital, Alain, Abu Dhabi, UAE Correspondence should be addressed to Suleiman Al-Hammadi; suleiman.alhammadi@uaeu.ac.ae Received 14 June 2020; Accepted 13 November 2020; Published 28 November 2020 Academic Editor: Aristo Vojdani Copyright © 2020 Suleiman Al-Hammadi et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. )e Bacillus Calmette–Guerin ´ (BCG) and rotavirus vaccines are live-attenuated preparations. In the United Arab Emirates, these products are universally administered to the young infants. )is unguided practice does not account for the children with immunodeficiency, which frequently manifests after the administration of these vaccines. We present here a young infant with immunodeficiency that developed disseminated tuberculosis infection and severe diarrhea due to these improper immunizations. Case Presentation. )is young infant was diagnosed at six months of age with “immunodeficiency type 19” (MIM#615617) due to homozygous nonsense variant, NM_000732.4 (CD3D):c.128G> A, p.Trp43∗ (variation Clin- Var#VCV000643120.1; pathogenic). )is variant creates premature stop-gain in CD3D (CD3 antigen, delta subunit, autosomal recessive; MIM#186790), resulting in loss-of-function. He also had “X-linked agammaglobulinemia” (MIM#300755) due to hemizygous missense variant, NM_001287344.1 (BTK):c.80G> A, p.Gly27Asp (novel). He had a sibling who passed away in infancy of unknown disease and family members with autoimmune disorders. Despite these clear clues, he was immunized with BCG at birth and rotavirus at 2 and 4 months. He was well in the first four months. He then developed high-fever, lymph- adenopathy, and refractory diarrhea. Stool was positive for rotavirus, and lymph node biopsy showed acid-fast bacilli, consistent with tuberculosis lymphadenitis. )ese infections were serious and markedly complicated his clinical course, which included bone marrow transplantation from a matched sibling. Conclusions. )ese unfortunate events could have been avoided by compiling the available clinical information. )is patient underscores the importance of implementing proper policies for BCG and rotavirus vaccinations. International registries of adverse events of universally administered vaccines are crucial. resulted in adverse events, especially with respect to ad- 1. Introduction ministering the BCG to children with yet unrevealed im- munodeficiency [2]. )ese cases justify implementing In the United Arab Emirates, the “Danish-SSI 1331 BCG live universal safe rules, restricting BCG and rotavirus vaccina- vaccine” (derived from attenuated Mycobacterium bovis tions without proper medical history, physical examination, cultures) has been administered to all newborns at birth since and preliminary investigation (e.g., complete blood count). 2005 [1]. In addition, the rotavirus live vaccine Rotarix )e American Academy of Pediatrics (AAP), the Centers (RV1) has been administered to all infants at 2 months and 4 for Disease Control and Prevention (CDC), and the World months of age since 2014 [1]. )ese unguided practices have 2 Case Reports in Immunology Health Organization (WHO) have all endorsed the rotavirus due to absent protein product. Pathologic variants of BTK vaccines [3–5]. )ese health organizations have also iden- (Bruton agammaglobulinemia tyrosine kinase; MIM#300300), on the other hand, cause “agammaglobu- tified immunodeficiency as a contraindication to the rota- virus vaccination. )eir statements, however, do not address linemia, X-linked 1 (MIM#300755) and “isolated growth the fundamental clinical question of “how to avoid its ad- hormone deficiency, type III, with agammaglobulinemia” ministering to infants with yet an undiagnosed immuno- (MIM#307200) [8]. His novel BTK variant had conflicting deficiency” [3–5]. )e authors here believe that health predictions of interpretation: MutationTaster: 0.810 (path- authorities who endorse live vaccines should also establish ogenic), LoFtool: 0.953 (pathogenic), and CADD: 7.6 clear strategies that prevent their improper use, especially in (benign). infants with immunodeficiency. We present this young )e parents, second cousins, had four healthy boys and infant with primary immunodeficiency to emphasize the one healthy daughter. )ey also had a daughter who passed importance of these raised points and encourage physicians away at the age of 4 months of an undetermined disease. )e to take the essential precautions prior to any use of atten- mother had four miscarriages in the first trimester. In ad- dition, she and six of her sisters had hypothyroidism; one uated vaccines. sister also had autoimmune hepatitis. Over the following six weeks, he continued to suffer from 2. Case Description high-fever, dyspnea (requiring oxygen), maculopapular )e following patient was an offspring of cousins and, thus, rash, severe oral thrush, poor feeding, severe diarrhea, expected to have an increased size of homozygous genomic failure-to-thrive, and E. coli urosepsis. On physical exami- segments. His clustered genetic variants and a brief de- nation, he had moderate hepatomegaly, mild splenomegaly, scription of his phenotype are discussed as follows. and palpable left axillary lymph nodes; the largest measured )is male infant was born at term and had uneventful about 2 cm in diameter. Neck, chest, and abdominal CT perinatal and postnatal periods until about 4 months of age. scans confirmed generalized lymphadenopathy, including His birth weight was 2.8 kg. Unfortunately, he was not his left axillary lymph nodes (Figure 1(b)). Excisional left axillary lymph node biopsy showed numerous acid-fast screened for the presence of TREC at birth, as current national neonatal screening programs in the UAE does not bacilli (AFB), consistent with tuberculous (TB) lymphade- include testing for primary immunodeficiencies. At birth, he nitis (Figure 2). As expected, IGRA (Interferon Gamma received the routine BCG and hepatitis B vaccines. At 2 and Release Assay) was negative. 4 months of age, he received the routine DTaP (diphtheria, His BCG-related lymphadenitis and systemic TB in- tetanus, acellular pertussis), HiB (haemophilus influenzae fection were treated with rifampicin, isoniazid, ethambutol, type b conjugate), and 13-valent pneumococcal conjugate, and pyridoxine. He was maintained on regular immuno- rotavirus (RV1,Rotarix ), and oral IP (inactivated polio) globulin infusion, trimethoprim-sulfamethoxazole for vaccines. At 4½ months, he developed severe respiratory Pneumocystis jiroveci prophylaxis, fluconazole for fungal infection and refractory diarrhea, which required hospi- prophylaxis, and broad-spectrum antibiotics. His brother talization and intravenous antibiotics. His blood and stool was a 10/10 HLA match. Bone marrow transplantation was performed before 8 months of age. cultures were negative. )e stool was positive for rotavirus. His chest radiographs showed bilateral infiltrations, and the thymus was not visible (Figure 1(a)). On admission, his 3. Discussion neutrophil count was 10.5 ×10 /L and lymphocyte count was 10.4 ×10 /L, with a normal hemoglobin concentration In its latest statement (2018), the WHO recommended BCG and platelet count. His serum IgE and IgA were unmea- vaccination in regions with a high prevalence of TB [9]. It surable, IgG <0.5 g/L (normal, 3.5 to 12.2), and IgM � 0.14 clarified “the available live attenuated (BCG) vaccines are (normal, 0.18 to 1.08). He was started on a regular intra- safe and effective”; “a single dose of BCG vaccine should be venous gammaglobulin infusion. )e results of given to all healthy neonates at birth”; “BCG vaccination is his lymphocyte immunophenotyping were as follows: contraindicated for persons with congenital cell-mediated or total lymphocyte count, 3,715/µL; CD3+, 96 cells/µL (nor- severe combined immunodeficiency...” [9]. )e definition of mal: 2,530 to 4,510); CD4+, 82 cells/µL (normal: 1,640 to a “healthy neonate” and a “way to avoid BCG vaccination to 2,980); CD8+, 1 cell/µL (normal: 780 to 1,500); CD19+, 3,000 a newborn with undiagnosed immunodeficiency,” however, cells/µL (normal: 1,160 to 2,420); and NK, 514 cells/µL. were not given. Diagnostic (whole) exome sequencing revealed two In a recent study of 349 BCG-vaccinated patients with pathogenic variants: homozygous NM_000732.4(CD3D): severe combined immunodeficiency (SCID), 34% had c.128G> A, p.Trp43∗ (VCV000643120.1; pathogenic; disseminated TB and 17% had localized TB [10]. )e au- https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi?REQ thors concluded “BCG vaccine has a very high rate of UEST�CCDS&DATA�CCDS8394) and hemizygous complications in patients with SCID, which increases NM_001287344.1 (BTK):c.80G> A, p.Gly27Asp (novel). morbidity and mortality rates. Until safer and more effi- Pathologic variants of CD3D (CD3 antigen, delta subunit, cient antituberculosis vaccines become available, delay in autosomal recessive; MIM#186790) cause “immunodefi- BCG vaccination should be considered to protect highly ciency type 19” (MIM#615617) [6, 7]. His CD3D variant vulnerable populations from preventable complications” creates a premature stop-gain, resulting in a loss-of-function [10]. Case Reports in Immunology 3 (a) (b) Figure 1: Panel A (4½ months of age): chest radiograph showing bilateral lung infiltrates and absent thymic shadow. Panel B (5 months of age): chest CT scan showing enlarged left axillary lymph node, measuring about 2 cm in diameter (arrowed). who received the vaccine at 10 weeks had higher BCG- specific CD4 cells compared to those who received it at birth [14]. It is also well-known that the genetically heterogeneous entity “Mendelian susceptibility to mycobacterial disease” confers susceptibility to BCG vaccines and other poorly virulent mycobacteria, such as nontuberculous mycobac- teria [15]. Its inheritance is autosomal recessive or X-linked recessive. )e former inheritance is common in cultures that encourage consanguineous marriages, such as the UAE [16]. Affected children typically present with severe or recurrent Figure 2: )e lymph node effaced and replaced by a sheet of mycobacterial infections. histiocytes; lymph node remnant seen as scattered lymphocytes and small lymphoid aggregates (arrow). )ere are necrotic foci within the histiocytes sheet (upper half of the picture). Ziehl–Neelsen stain 4. Conclusion showing numerous acid-fast bacilli (the red box region). )e acid- fast bacilli are red color rods. BCG and rotavirus vaccines should be avoided if any finding on the medical history, physical examination, or laboratory Similarly, the adverse events of rotavirus vaccines in investigation suggests animpaired immunity. It is essential infants with SCID are numerous (recently reviewed in to attain a detailed history on all family members, including reference [11]). A recent study from England showed any adverse events to vaccines. Medical records should alert infants with unidentified SCID at the time of rotavirus healthcare providers of any family member with an adverse vaccination had prolonged diarrhea due to vaccine event or contraindication to vaccination [2]. More impor- strains for over 7 weeks [12]. A case report from Italy tantly, family counseling should enforce the need for parents described a patient with SCID and rotavirus infection to share important medical information with their health- from a vaccine-derived strain, which was detected by care providers. Side effects to live vaccines should be con- enzyme immunoassays and RT-PCR in stool specimens sidered in young infants with persistent diarrhea or high- for five months. )e infection was resolved only after a fever, as these symptoms may herald the other clinical complete immune reconstitution by bone marrow manifestations of impaired immunity. Finally, local regis- transplantation [13]. tries of primary immune deficiency are necessary for esti- Most infants with SCID become symptomatic in the first mating the birth prevalence of these disorders in the few weeks of life, alerting physicians to avoid administering community. )is information aids the development and the live vaccines. Delaying these vaccinations deserves global implementation of BCG and rotavirus vaccination policy. systematic studies. In one randomized prospective trial, the Randomized controlled trials are needed to investigate the response to BCG was compared between vaccinations at safety and efficacy of late versus early administration of liver birth and vaccinations at 10 weeks of age. )e young infants vaccines to the neonate. 4 Case Reports in Immunology complications, risks, and vaccination policies,” Journal of Data Availability Allergy and Clinical Immunology, vol. 133, no. 4, pp. 1134– 1141, 2014. )e data used to support the findings of the study are [11] M. Chiu, C. Bao, and M. Sadarangani, “Dilemmas with ro- available from the corresponding author upon request. tavirus vaccine,” 5e Pediatric Infectious Disease Journal, vol. 38, pp. S43–S46, 2019. Consent [12] C. M. Gower, J. Dunning, S. Nawaz, D. Allen, M. E. Ramsay, and S. Ladhani, “Vaccine-derived rotavirus strains in infants )e patient’s father provided consent. in England,” Archives of Disease in Childhood, vol. 105, no. 6, pp. 553–557, 2019. Conflicts of Interest [13] M. A. De Francesco, G. Ianiro, M. Monini et al., “Persistent infection with rotavirus vaccine strain in severe combined )e authors declare that they have no conflicts of interest. immunodeficiency (SCID) child: is rotavirus vaccination in SCID children a Janus Face?” Vaccines (Basel), vol. 7, no. 4, Authors’ Contributions [14] B. M. N. Kagina, B. Abel, M. Bowmaker et al., “Delaying BCG vaccination from birth to 10 weeks of age may result in an S.A-H. and A-K.S conceptualized the study; N.S.A., G.A.G., enhanced memory CD4 T cell response,” Vaccine, vol. 27, H.A.D., A.S.E., and H.M.S. were responsible for clinical data; no. 40, pp. 5488–5495, 2009. F.A. was responsible for variant analysis; A-K.S. wrote and [15] L.-H. Wang, C.-L. Yen, T.-C. Chang, C.-C. Liu, and prepared the original draft; S.A-H. and F.A. wrote, reviewed, C.-C. Shieh, “Impact of molecular diagnosis on treating and edited the manuscript. All authors were major con- mendelian susceptibility to mycobacterial diseases,” Journal of tributors to the manuscript. All authors read and approved Microbiology, Immunology and Infection, vol. 45, no. 6, the final draft. pp. 411–417, 2012. [16] J. Bustamante, C. Picard, S. Boisson-Dupuis, L. Abel, and J.-L. Casanova, “Genetic lessons learned from X-linked Acknowledgments mendelian susceptibility to mycobacterial diseases,” Annals of the New York Academy of Sciences, vol. 1246, no. 1, pp. 92–101, )e authors are grateful to Tawam Hospital staff and services for their valuable support of this critically ill patient. References [1] United Arab Emirates: WHO and UNICEF estimates of immunization coverage: 2018 revision; https://www.who.int/ immunization/monitoring_surveillance/data/are.pdf. [2] S. Al-Hammadi, A. R. Alsuwaidi, E. T. Alshamsi, G. A. Ghatasheh, and A. K. Souid, “Disseminated Bacillus Calmette-Guerin ´ (BCG) infections in infants with immuno- deficiency,” BMC Research Notes, vol. 10, p. 177, 2017. [3] Committee on Infectious Diseases; American Academy of Pediatrics, “Prevention of rotavirus disease: updated guide- lines for use of rotavirus vaccine,” Pediatrics, vol. 123, pp. 1412–1420, 2009. [4] “Rotavirus vaccines WHO position paper: january 2013- recommendations,” Vaccine, vol. 31, pp. 6170–61701, 2013. [5] https://www.cdc.gov/vaccines/vpd/rotavirus/public/index. html. [6] H. K. Dadi, A. J. Simon, and C. M. Roifman, “Effect of CD3δ deficiency on maturation of α/β and c/δ T-cell lineages in severe combined immunodeficiency,” New England Journal of Medicine, vol. 349, no. 19, pp. 1821–1828, 2003. [7] G. d. S. Basile, F. Geissmann, E. Flori et al., “Severe combined immunodeficiency caused by deficiency in either the δ or the ε subunit of CD3,” Journal of Clinical Investigation, vol. 114, no. 10, pp. 1512–1517, 2004. [8] Q. Zhu, M. Zhang, J. Winkelstein, S.-H. Chen, and H. D. Ochs, “Unique mutations of Bruton’s tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families,” Human Molecular Genetics, vol. 3, no. 10, pp. 1899-1900, 1994. [9] World Health Organization, “BCG vaccine: WHO position paper, february 2018-recommendations,” Vaccine, vol. 36, no. 24, pp. 3408–3410, 2018. [10] B. E. Marciano, C.-Y. Huang, G. Joshi et al., “BCG vaccination in patients with severe combined immunodeficiency: http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Immunology Hindawi Publishing Corporation

Adverse Events of the BCG (Bacillus Calmette–Guérin) and Rotavirus Vaccines in a Young Infant with Inborn Error of Immunity

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Copyright © 2020 Suleiman Al-Hammadi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Case Reports in Immunology Volume 2020, Article ID 8857152, 4 pages https://doi.org/10.1155/2020/8857152 Case Report Adverse Events of the BCG (Bacillus Calmette–Guerin) and Rotavirus Vaccines in a Young Infant with Inborn Error of Immunity 1 2 2 Suleiman Al-Hammadi , Najla S. Alkuwaiti, Ghassan A. Ghatasheh, 2 2 3 Huda Al Dhanhani, Hiba M. Shendi, Abdulghani S. Elomami, 1 1 Farida Almarzooqi , and Abdul-Kader Souid Department of Pediatrics, College of Medicine and Health Sciences, UAE University, Abu Dhabi, UAE Department of Pediatrics, Tawam Hospital, Alain, Abu Dhabi, UAE Department of Pathology, Tawam Hospital, Alain, Abu Dhabi, UAE Correspondence should be addressed to Suleiman Al-Hammadi; suleiman.alhammadi@uaeu.ac.ae Received 14 June 2020; Accepted 13 November 2020; Published 28 November 2020 Academic Editor: Aristo Vojdani Copyright © 2020 Suleiman Al-Hammadi et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. )e Bacillus Calmette–Guerin ´ (BCG) and rotavirus vaccines are live-attenuated preparations. In the United Arab Emirates, these products are universally administered to the young infants. )is unguided practice does not account for the children with immunodeficiency, which frequently manifests after the administration of these vaccines. We present here a young infant with immunodeficiency that developed disseminated tuberculosis infection and severe diarrhea due to these improper immunizations. Case Presentation. )is young infant was diagnosed at six months of age with “immunodeficiency type 19” (MIM#615617) due to homozygous nonsense variant, NM_000732.4 (CD3D):c.128G> A, p.Trp43∗ (variation Clin- Var#VCV000643120.1; pathogenic). )is variant creates premature stop-gain in CD3D (CD3 antigen, delta subunit, autosomal recessive; MIM#186790), resulting in loss-of-function. He also had “X-linked agammaglobulinemia” (MIM#300755) due to hemizygous missense variant, NM_001287344.1 (BTK):c.80G> A, p.Gly27Asp (novel). He had a sibling who passed away in infancy of unknown disease and family members with autoimmune disorders. Despite these clear clues, he was immunized with BCG at birth and rotavirus at 2 and 4 months. He was well in the first four months. He then developed high-fever, lymph- adenopathy, and refractory diarrhea. Stool was positive for rotavirus, and lymph node biopsy showed acid-fast bacilli, consistent with tuberculosis lymphadenitis. )ese infections were serious and markedly complicated his clinical course, which included bone marrow transplantation from a matched sibling. Conclusions. )ese unfortunate events could have been avoided by compiling the available clinical information. )is patient underscores the importance of implementing proper policies for BCG and rotavirus vaccinations. International registries of adverse events of universally administered vaccines are crucial. resulted in adverse events, especially with respect to ad- 1. Introduction ministering the BCG to children with yet unrevealed im- munodeficiency [2]. )ese cases justify implementing In the United Arab Emirates, the “Danish-SSI 1331 BCG live universal safe rules, restricting BCG and rotavirus vaccina- vaccine” (derived from attenuated Mycobacterium bovis tions without proper medical history, physical examination, cultures) has been administered to all newborns at birth since and preliminary investigation (e.g., complete blood count). 2005 [1]. In addition, the rotavirus live vaccine Rotarix )e American Academy of Pediatrics (AAP), the Centers (RV1) has been administered to all infants at 2 months and 4 for Disease Control and Prevention (CDC), and the World months of age since 2014 [1]. )ese unguided practices have 2 Case Reports in Immunology Health Organization (WHO) have all endorsed the rotavirus due to absent protein product. Pathologic variants of BTK vaccines [3–5]. )ese health organizations have also iden- (Bruton agammaglobulinemia tyrosine kinase; MIM#300300), on the other hand, cause “agammaglobu- tified immunodeficiency as a contraindication to the rota- virus vaccination. )eir statements, however, do not address linemia, X-linked 1 (MIM#300755) and “isolated growth the fundamental clinical question of “how to avoid its ad- hormone deficiency, type III, with agammaglobulinemia” ministering to infants with yet an undiagnosed immuno- (MIM#307200) [8]. His novel BTK variant had conflicting deficiency” [3–5]. )e authors here believe that health predictions of interpretation: MutationTaster: 0.810 (path- authorities who endorse live vaccines should also establish ogenic), LoFtool: 0.953 (pathogenic), and CADD: 7.6 clear strategies that prevent their improper use, especially in (benign). infants with immunodeficiency. We present this young )e parents, second cousins, had four healthy boys and infant with primary immunodeficiency to emphasize the one healthy daughter. )ey also had a daughter who passed importance of these raised points and encourage physicians away at the age of 4 months of an undetermined disease. )e to take the essential precautions prior to any use of atten- mother had four miscarriages in the first trimester. In ad- dition, she and six of her sisters had hypothyroidism; one uated vaccines. sister also had autoimmune hepatitis. Over the following six weeks, he continued to suffer from 2. Case Description high-fever, dyspnea (requiring oxygen), maculopapular )e following patient was an offspring of cousins and, thus, rash, severe oral thrush, poor feeding, severe diarrhea, expected to have an increased size of homozygous genomic failure-to-thrive, and E. coli urosepsis. On physical exami- segments. His clustered genetic variants and a brief de- nation, he had moderate hepatomegaly, mild splenomegaly, scription of his phenotype are discussed as follows. and palpable left axillary lymph nodes; the largest measured )is male infant was born at term and had uneventful about 2 cm in diameter. Neck, chest, and abdominal CT perinatal and postnatal periods until about 4 months of age. scans confirmed generalized lymphadenopathy, including His birth weight was 2.8 kg. Unfortunately, he was not his left axillary lymph nodes (Figure 1(b)). Excisional left axillary lymph node biopsy showed numerous acid-fast screened for the presence of TREC at birth, as current national neonatal screening programs in the UAE does not bacilli (AFB), consistent with tuberculous (TB) lymphade- include testing for primary immunodeficiencies. At birth, he nitis (Figure 2). As expected, IGRA (Interferon Gamma received the routine BCG and hepatitis B vaccines. At 2 and Release Assay) was negative. 4 months of age, he received the routine DTaP (diphtheria, His BCG-related lymphadenitis and systemic TB in- tetanus, acellular pertussis), HiB (haemophilus influenzae fection were treated with rifampicin, isoniazid, ethambutol, type b conjugate), and 13-valent pneumococcal conjugate, and pyridoxine. He was maintained on regular immuno- rotavirus (RV1,Rotarix ), and oral IP (inactivated polio) globulin infusion, trimethoprim-sulfamethoxazole for vaccines. At 4½ months, he developed severe respiratory Pneumocystis jiroveci prophylaxis, fluconazole for fungal infection and refractory diarrhea, which required hospi- prophylaxis, and broad-spectrum antibiotics. His brother talization and intravenous antibiotics. His blood and stool was a 10/10 HLA match. Bone marrow transplantation was performed before 8 months of age. cultures were negative. )e stool was positive for rotavirus. His chest radiographs showed bilateral infiltrations, and the thymus was not visible (Figure 1(a)). On admission, his 3. Discussion neutrophil count was 10.5 ×10 /L and lymphocyte count was 10.4 ×10 /L, with a normal hemoglobin concentration In its latest statement (2018), the WHO recommended BCG and platelet count. His serum IgE and IgA were unmea- vaccination in regions with a high prevalence of TB [9]. It surable, IgG <0.5 g/L (normal, 3.5 to 12.2), and IgM � 0.14 clarified “the available live attenuated (BCG) vaccines are (normal, 0.18 to 1.08). He was started on a regular intra- safe and effective”; “a single dose of BCG vaccine should be venous gammaglobulin infusion. )e results of given to all healthy neonates at birth”; “BCG vaccination is his lymphocyte immunophenotyping were as follows: contraindicated for persons with congenital cell-mediated or total lymphocyte count, 3,715/µL; CD3+, 96 cells/µL (nor- severe combined immunodeficiency...” [9]. )e definition of mal: 2,530 to 4,510); CD4+, 82 cells/µL (normal: 1,640 to a “healthy neonate” and a “way to avoid BCG vaccination to 2,980); CD8+, 1 cell/µL (normal: 780 to 1,500); CD19+, 3,000 a newborn with undiagnosed immunodeficiency,” however, cells/µL (normal: 1,160 to 2,420); and NK, 514 cells/µL. were not given. Diagnostic (whole) exome sequencing revealed two In a recent study of 349 BCG-vaccinated patients with pathogenic variants: homozygous NM_000732.4(CD3D): severe combined immunodeficiency (SCID), 34% had c.128G> A, p.Trp43∗ (VCV000643120.1; pathogenic; disseminated TB and 17% had localized TB [10]. )e au- https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi?REQ thors concluded “BCG vaccine has a very high rate of UEST�CCDS&DATA�CCDS8394) and hemizygous complications in patients with SCID, which increases NM_001287344.1 (BTK):c.80G> A, p.Gly27Asp (novel). morbidity and mortality rates. Until safer and more effi- Pathologic variants of CD3D (CD3 antigen, delta subunit, cient antituberculosis vaccines become available, delay in autosomal recessive; MIM#186790) cause “immunodefi- BCG vaccination should be considered to protect highly ciency type 19” (MIM#615617) [6, 7]. His CD3D variant vulnerable populations from preventable complications” creates a premature stop-gain, resulting in a loss-of-function [10]. Case Reports in Immunology 3 (a) (b) Figure 1: Panel A (4½ months of age): chest radiograph showing bilateral lung infiltrates and absent thymic shadow. Panel B (5 months of age): chest CT scan showing enlarged left axillary lymph node, measuring about 2 cm in diameter (arrowed). who received the vaccine at 10 weeks had higher BCG- specific CD4 cells compared to those who received it at birth [14]. It is also well-known that the genetically heterogeneous entity “Mendelian susceptibility to mycobacterial disease” confers susceptibility to BCG vaccines and other poorly virulent mycobacteria, such as nontuberculous mycobac- teria [15]. Its inheritance is autosomal recessive or X-linked recessive. )e former inheritance is common in cultures that encourage consanguineous marriages, such as the UAE [16]. Affected children typically present with severe or recurrent Figure 2: )e lymph node effaced and replaced by a sheet of mycobacterial infections. histiocytes; lymph node remnant seen as scattered lymphocytes and small lymphoid aggregates (arrow). )ere are necrotic foci within the histiocytes sheet (upper half of the picture). Ziehl–Neelsen stain 4. Conclusion showing numerous acid-fast bacilli (the red box region). )e acid- fast bacilli are red color rods. BCG and rotavirus vaccines should be avoided if any finding on the medical history, physical examination, or laboratory Similarly, the adverse events of rotavirus vaccines in investigation suggests animpaired immunity. It is essential infants with SCID are numerous (recently reviewed in to attain a detailed history on all family members, including reference [11]). A recent study from England showed any adverse events to vaccines. Medical records should alert infants with unidentified SCID at the time of rotavirus healthcare providers of any family member with an adverse vaccination had prolonged diarrhea due to vaccine event or contraindication to vaccination [2]. More impor- strains for over 7 weeks [12]. A case report from Italy tantly, family counseling should enforce the need for parents described a patient with SCID and rotavirus infection to share important medical information with their health- from a vaccine-derived strain, which was detected by care providers. Side effects to live vaccines should be con- enzyme immunoassays and RT-PCR in stool specimens sidered in young infants with persistent diarrhea or high- for five months. )e infection was resolved only after a fever, as these symptoms may herald the other clinical complete immune reconstitution by bone marrow manifestations of impaired immunity. Finally, local regis- transplantation [13]. tries of primary immune deficiency are necessary for esti- Most infants with SCID become symptomatic in the first mating the birth prevalence of these disorders in the few weeks of life, alerting physicians to avoid administering community. )is information aids the development and the live vaccines. Delaying these vaccinations deserves global implementation of BCG and rotavirus vaccination policy. systematic studies. In one randomized prospective trial, the Randomized controlled trials are needed to investigate the response to BCG was compared between vaccinations at safety and efficacy of late versus early administration of liver birth and vaccinations at 10 weeks of age. )e young infants vaccines to the neonate. 4 Case Reports in Immunology complications, risks, and vaccination policies,” Journal of Data Availability Allergy and Clinical Immunology, vol. 133, no. 4, pp. 1134– 1141, 2014. )e data used to support the findings of the study are [11] M. Chiu, C. Bao, and M. Sadarangani, “Dilemmas with ro- available from the corresponding author upon request. tavirus vaccine,” 5e Pediatric Infectious Disease Journal, vol. 38, pp. S43–S46, 2019. Consent [12] C. M. Gower, J. Dunning, S. Nawaz, D. Allen, M. E. Ramsay, and S. Ladhani, “Vaccine-derived rotavirus strains in infants )e patient’s father provided consent. in England,” Archives of Disease in Childhood, vol. 105, no. 6, pp. 553–557, 2019. Conflicts of Interest [13] M. A. De Francesco, G. Ianiro, M. Monini et al., “Persistent infection with rotavirus vaccine strain in severe combined )e authors declare that they have no conflicts of interest. immunodeficiency (SCID) child: is rotavirus vaccination in SCID children a Janus Face?” Vaccines (Basel), vol. 7, no. 4, Authors’ Contributions [14] B. M. N. Kagina, B. Abel, M. Bowmaker et al., “Delaying BCG vaccination from birth to 10 weeks of age may result in an S.A-H. and A-K.S conceptualized the study; N.S.A., G.A.G., enhanced memory CD4 T cell response,” Vaccine, vol. 27, H.A.D., A.S.E., and H.M.S. were responsible for clinical data; no. 40, pp. 5488–5495, 2009. F.A. was responsible for variant analysis; A-K.S. wrote and [15] L.-H. Wang, C.-L. Yen, T.-C. Chang, C.-C. Liu, and prepared the original draft; S.A-H. and F.A. wrote, reviewed, C.-C. Shieh, “Impact of molecular diagnosis on treating and edited the manuscript. All authors were major con- mendelian susceptibility to mycobacterial diseases,” Journal of tributors to the manuscript. All authors read and approved Microbiology, Immunology and Infection, vol. 45, no. 6, the final draft. pp. 411–417, 2012. [16] J. Bustamante, C. Picard, S. Boisson-Dupuis, L. Abel, and J.-L. Casanova, “Genetic lessons learned from X-linked Acknowledgments mendelian susceptibility to mycobacterial diseases,” Annals of the New York Academy of Sciences, vol. 1246, no. 1, pp. 92–101, )e authors are grateful to Tawam Hospital staff and services for their valuable support of this critically ill patient. References [1] United Arab Emirates: WHO and UNICEF estimates of immunization coverage: 2018 revision; https://www.who.int/ immunization/monitoring_surveillance/data/are.pdf. [2] S. Al-Hammadi, A. R. Alsuwaidi, E. T. Alshamsi, G. A. Ghatasheh, and A. K. Souid, “Disseminated Bacillus Calmette-Guerin ´ (BCG) infections in infants with immuno- deficiency,” BMC Research Notes, vol. 10, p. 177, 2017. [3] Committee on Infectious Diseases; American Academy of Pediatrics, “Prevention of rotavirus disease: updated guide- lines for use of rotavirus vaccine,” Pediatrics, vol. 123, pp. 1412–1420, 2009. [4] “Rotavirus vaccines WHO position paper: january 2013- recommendations,” Vaccine, vol. 31, pp. 6170–61701, 2013. [5] https://www.cdc.gov/vaccines/vpd/rotavirus/public/index. html. [6] H. K. Dadi, A. J. Simon, and C. M. Roifman, “Effect of CD3δ deficiency on maturation of α/β and c/δ T-cell lineages in severe combined immunodeficiency,” New England Journal of Medicine, vol. 349, no. 19, pp. 1821–1828, 2003. [7] G. d. S. Basile, F. Geissmann, E. Flori et al., “Severe combined immunodeficiency caused by deficiency in either the δ or the ε subunit of CD3,” Journal of Clinical Investigation, vol. 114, no. 10, pp. 1512–1517, 2004. [8] Q. Zhu, M. Zhang, J. Winkelstein, S.-H. Chen, and H. D. Ochs, “Unique mutations of Bruton’s tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families,” Human Molecular Genetics, vol. 3, no. 10, pp. 1899-1900, 1994. [9] World Health Organization, “BCG vaccine: WHO position paper, february 2018-recommendations,” Vaccine, vol. 36, no. 24, pp. 3408–3410, 2018. [10] B. E. Marciano, C.-Y. Huang, G. Joshi et al., “BCG vaccination in patients with severe combined immunodeficiency:

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