{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:40:17Z","timestamp":1760146817297,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Infectious Disease Reports"],"abstract":"<jats:p>Background\/Objectives: Common Variable Immunodeficiency Disease (CVID) and other immunodeficiencies can present in subtle and variable ways. Whether or not a genetic lesion can be identified, there are not well understood biomarkers that quantitatively describe how severe a deficiency is. Here we discuss two possible ranking systems, CD4\/CD8 T cell ratios and Immune Health Grades, and how such data maybe applicable to some immunodeficiencies. Methods: This is not a systematic review, but we identify papers relating to immunodeficiencies with enough data to comment on the CD4\/CD8 and Immune Health Grade. We also summarized relevant data publicly available from USIDNET, a website that compiles data on immunodeficiencies, and provide two new cases that illustrate ways that this information can alter clinical assessment. Results: We review the HIV literature on CD4\/CD8 T cell data and how this correlates with both immunologic function and comorbidity better than CD4 count alone. The ratio aslso relates to a new system called Immune Health Grades (IHG) derived from young adult to elderly subjects from many NIH cohorts without HIV. CVID is often thought of as an antibody problem, but in fact most patients also have low CD4\/CD8 ratio and other cellular abnormalities. We review IDNET to categorize nine molecular immunodeficiencies including two subcategories of CVID into low, normal, or high ratios. Finally, we present two new cases in the literature of patients with recurrent infection and discuss how viewing the cases through the \u201clens\u201d of CD4\/CD8 ratio and IHG can facilitate clinical decisions. Conclusions: Emerging data suggests at least some immunodeficiencies can be grouped by how abnormal their CD4\/CD8 ratio or IHG. This represents a clinically available biomarker that can be tracked to see if the condition is worsening or not.<\/jats:p>","DOI":"10.3390\/idr16060097","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T06:26:12Z","timestamp":1734416772000},"page":"1230-1239","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Using T-Cell Subsets to Better Characterize Immunoresiliency and Immunodeficiency in Patients with Recurrent Infections"],"prefix":"10.3390","volume":"16","author":[{"given":"Justine","family":"Hung","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5657-0980","authenticated-orcid":false,"given":"Bryan","family":"Vonasek","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tri","family":"Vo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Michigan State University, East Lansing, MI 48842, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0454-895X","authenticated-orcid":false,"given":"Rob","family":"Striker","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.gendis.2019.10.002","article-title":"Recent advances in elucidating the genetics of common variable immunodeficiency","volume":"7","author":"Aggarwal","year":"2020","journal-title":"Genes Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.jaci.2021.08.021","article-title":"Immunologic resilience and COVID-19 survival advantage","volume":"148","author":"Lee","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3286","DOI":"10.1038\/s41467-023-38238-6","article-title":"Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection","volume":"14","author":"Ahuja","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Serrano-Villar, S., Sainz, T., Lee, S.A., Hunt, P.W., Sinclair, E., Shacklett, B.L., Ferre, A.L., Hayes, T.L., Somsouk, M., and Hsue, P.Y. (2014). HIV-infected individuals with low CD4\/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004078"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1093\/jnci\/djac053","article-title":"CD4\/CD8 Ratio and Cancer Risk Among Adults With HIV","volume":"114","author":"Castilho","year":"2022","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1093\/cid\/ciad136","article-title":"CD4\/CD8 ratio during HIV treatment: Time for routine monitoring?","volume":"76","author":"Ron","year":"2023","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1056\/NEJMoa2202348","article-title":"Reappraisal of Idiopathic CD4 Lymphocytopenia at 30 Years","volume":"388","author":"Lisco","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1093\/cid\/ciaa1137","article-title":"CD4\/CD8 Ratio and the Risk of Kaposi Sarcoma or Non-Hodgkin Lymphoma in the Context of Efficiently Treated Human Immunodeficiency Virus (HIV) Infection: A Collaborative Analysis of 20 European Cohort Studies","volume":"73","author":"Caby","year":"2021","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4737","DOI":"10.1245\/s10434-023-13213-z","article-title":"Duration of Time CD4\/CD8 Ratio is Below 0.5 is Associated with Progression to Anal Cancer in Patients with HIV and High-Grade Dysplasia","volume":"30","author":"Karim","year":"2023","journal-title":"Ann. Surg. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1093\/gerona\/glu018","article-title":"CD4:8 Ratio >5 Is Associated with a Dominant Naive T-Cell Phenotype and Impaired Physical Functioning in CMV-Seropositive Very Elderly People: Results from the BELFRAIL Study","volume":"70","author":"Adriaensen","year":"2015","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1093\/cid\/ciy176","article-title":"Incomplete Recovery of CD4 Cell Count, CD4 Percentage, and CD4\/CD8 Ratio in Patients with Human Immunodeficiency Virus Infection and Suppressed Viremia During Long-term Antiretroviral Therapy","volume":"67","author":"Mutoh","year":"2018","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jinf.2017.06.007","article-title":"Respiratory syncytial virus in adults with severe acute respiratory illness in a high HIV prevalence setting","volume":"75","author":"Moyes","year":"2017","journal-title":"J. Infect."},{"key":"ref_13","first-page":"200","article-title":"Agammaglobulinemia","volume":"66","author":"Janeway","year":"1953","journal-title":"Trans. Assoc. Am. Physicians"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3932","DOI":"10.4049\/jimmunol.178.6.3932","article-title":"Unravelling the complexity of T cell abnormalities in common variable immunodeficiency","volume":"178","author":"Giovannetti","year":"2007","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1006\/clim.1999.4725","article-title":"Common Variable Immunodeficiency: Clinical and Immunological Features of 248 Patients","volume":"92","author":"Bodian","year":"1999","journal-title":"Clin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1182\/blood-2011-09-377945","article-title":"Morbidity and mortality in common variable immune deficiency over 4 decades","volume":"119","author":"Resnick","year":"2012","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s00005-016-0414-x","article-title":"Indications to Epigenetic Dysfunction in the Pathogenesis of Common Variable Immunodeficiency","volume":"65","author":"Rae","year":"2017","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"108931","DOI":"10.1016\/j.clim.2022.108931","article-title":"Health-related quality of life in primary immunodeficiencies: Impact of delayed diagnosis and treatment burden","volume":"236","author":"Anderson","year":"2022","journal-title":"Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.iac.2020.03.002","article-title":"The Importance of Primary Immune Deficiency Registries","volume":"40","author":"Lopes","year":"2020","journal-title":"Immunol. Allergy Clin. N. Am."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1067\/mai.2002.122466","article-title":"Primary immunodeficiency disorders: Antibody deficiency","volume":"109","author":"Ballow","year":"2002","journal-title":"J Allergy Clin Immunol."},{"key":"ref_21","unstructured":"(2023, May 09). USIDNET. Available online: https:\/\/usidnet.org\/."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4475","DOI":"10.4049\/jimmunol.170.9.4475","article-title":"Phosphatidylinositol 3-Kinase Regulates the CD4\/CD8 T Cell Differentiation Ratio","volume":"170","author":"Barber","year":"2003","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Shelyakin, P.V., Lupyr, K.R., Egorov, E.S., Kofiadi, I.A., Staroverov, D.B., Kasatskaya, S.A., Kriukova, V.V., Shagina, I.A., Merzlyak, E.M., and Nakonechnaya, T.O. (2021). Na\u00efve Regulatory T Cell Subset Is Altered in X-Linked Agammaglobulinemia. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.697307"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jaci.2014.06.001","article-title":"MHC class I and II deficiencies","volume":"134","author":"Hanna","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"D\u0105browska-Leonik, N., Pi\u0105tosa, B., S\u0142omi\u0144ska, E., Bohynikova, N., Bernat-Sitarz, K., Bernatowska, E., Wolska-Ku\u015bnierz, B., Ka\u0142wak, K., Ko\u0142tan, S., and D\u0105browska, A. (2022). National experience with adenosine deaminase deficiency related SCID in Polish children. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1058623"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Aluri, J., Desai, M., Gupta, M., Dalvi, A., Terance, A., Rosenzweig, S.D., Stoddard, J.L., Niemela, J.E., Tamankar, V., and Mhatre, S. (2019). Clinical, Immunological, and Molecular Findings in 57 Patients with Severe Combined Immunodeficiency (SCID) from India. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00023"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Schepp, J., Chou, J., Skrabl-Baumgartner, A., Arkwright, P.D., Engelhardt, K.R., Hambleton, S., Morio, T., R\u00f6ther, E., Warnatz, K., and Geha, R. (2017). 14\u2009Years after Discovery: Clinical Follow-up on 15 Patients with Inducible Co-Stimulator Deficiency. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00964"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1182\/blood-2005-07-2955","article-title":"Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency","volume":"107","author":"Warnatz","year":"2006","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/j.jaci.2018.02.055","article-title":"Phenotype, penetrance, and treatment of 133 CTLA-4-insufficient subjects","volume":"142","author":"Schwab","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/j.1365-2249.2004.02409.x","article-title":"Early deficit of lymphocytes in Wiskott\u2013Aldrich syndrome: Possible role of WASP in human lymphocyte maturation","volume":"136","author":"Park","year":"2004","journal-title":"Clin. Exp. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"O\u2019Connell, A.E., Volpi, S., Dobbs, K., Fiorini, C., Tsitsikov, E., de Boer, H., Barlan, I.B., Despotovic, J.M., Espinosa-Rosales, F.J., and Hanson, I.C. (2014). Next generation sequencing reveals skewing of the T and B cell receptor repertoires in patients with wiskott-Aldrich syndrome. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00340"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/s41435-022-00166-8","article-title":"Identification of a novel MAGT1 mutation supports a diagnosis of XMEN disease","volume":"23","author":"Watson","year":"2022","journal-title":"Genes Immun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1046\/j.1365-2249.2002.01830.x","article-title":"Deficiencies in CD4+ and CD8+ T cell subsets in ataxia telangiectasia","volume":"129","author":"Schubert","year":"2002","journal-title":"Clin. Exp. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Sharifinejad, N., Jamee, M., Zaki-Dizaji, M., Lo, B., Shaghaghi, M., Mohammadi, H., Jadidi-Niaragh, F., Shaghaghi, S., Yazdani, R., and Abolhassani, H. (2020). Clinical, Immunological, and Genetic Features in 49 Patients with ZAP-70 Deficiency: A Systematic Review. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00831"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/ni902","article-title":"Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency","volume":"4","author":"Grimbacher","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Shaheen, Z.R., Williams, S.J.A., and Binstadt, B.A. (2021). Case Report: A Novel TNFAIP3 Mutation Causing Haploinsufficiency of A20 With a Lupus-Like Phenotype. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.629457"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1164\/ajrccm\/139.6.1446","article-title":"The effects of cigarette smoking on t cell subsets: A population-based survey of healthy caucasians","volume":"139","author":"Tollerud","year":"1989","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1600-0404.1995.tb00147.x","article-title":"T cell subsets in multiple sclerosis: A serial study","volume":"92","author":"Calopa","year":"1995","journal-title":"Acta Neurol. Scand."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1111\/j.1365-2249.2007.03429.x","article-title":"T lymphocyte subset profile and serum alpha-1-antitrypsin in pathogenesis of chronic obstructive lung disease","volume":"149","author":"Gupta","year":"2007","journal-title":"Clin. Exp. Immunol."}],"container-title":["Infectious Disease Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2036-7449\/16\/6\/97\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:52:44Z","timestamp":1760115164000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2036-7449\/16\/6\/97"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,16]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["idr16060097"],"URL":"https:\/\/doi.org\/10.3390\/idr16060097","relation":{},"ISSN":["2036-7449"],"issn-type":[{"type":"electronic","value":"2036-7449"}],"subject":[],"published":{"date-parts":[[2024,12,16]]}}}