The DOI matches its Crossref record; 51 of the 52 references it cites were found in a registry or an index.
Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza
Open accessAbstract
BACKGROUND: Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza. METHODS: Sixteen cases of fatal influenza A(H1N1) infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH, using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole-exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral-transduced NK-92 natural killer (NK) cells. RESULTS: Despite several lacking variables, cases of influenza A(H1N1) infection met 44% and 81% of modified HLH-2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS. CONCLUSIONS: This cohort of fatal influenza A(H1N1) infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among individuals with influenza A(H1N1) infection.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The pattern of cytokine elevations varies on the basis of such factors as the microbiome, genetic features, and underlying disorders.”
From Cytokine storm (2020) · cites this paper as [30]
In the citing paper
“Furthermore, retrospective analyses of data from persons who died from coagulopathies and hemophagocytosis during the H1N1 influenza pandemic of 2009 revealed germline mutations previously associated with HLH-associated cytokine storm.30”
From Cytokine storm (2020) · cites this paper as [30]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
HLH‐2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis
Henter, J., Horne, A., Aricò, M., Egeler, R. M., Filipovich, A. H., Imashuku, S., Ladisch, S., McClain, K. L., Webb, D. K. H., Winiarski, J. H., et al. (2006) · Pediatric Blood & Cancer · doi:10.1002/pbc.21039 · Cited by 5,396
Fardet, L., Galicier, L., Lambotte, O., Marzac, C., Aumont, C., Chahwan, D., Coppo, P., & Hejblum, G. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38690 · Cited by 1,508
Ravelli, A., Minoia, F., Davì, S., Horne, A., Bovis, F., Pistorio, A., Aricò, M., Avčin, T., Behrens, E. M., Benedetti, F. D., et al. (2015) · Arthritis & Rheumatology · doi:10.1002/art.39332 · Cited by 770
Self-citationIdentification of the homologous beige and Chediak–Higashi syndrome genes
Barbosa, M. D. F. S., Nguyen, Q. A., Tchernev, V. T., Ashley, J., Detter, J. C., Blaydes, S. M., Brandt, S. J., Chotai, D., Hodgman, C. T., Solari, R. C. E., et al. (1996) · Nature · doi:10.1038/382262a0 · Cited by 549
Lung Pathology in Fatal Novel Human Influenza A (H1N1) Infection
Mauad, T., Hajjar, L. A., Callegari, G. D., da Silva, L. F. F., Schout, D., Galas, F. R. B. G., Alves, V. A. F., Malheiros, D. M. A. C., Auler, J. O. C., Ferreira, A. F., et al. (2010) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200909-1420oc · Cited by 547
The structural basis for membrane binding and pore formation by lymphocyte perforin
Law, R. H. P., Lukoyanova, N., Voskoboinik, I., Caradoc-Davies, T. T., Baran, K., Dunstone, M. A., D’Angelo, M. E., Orlova, E. V., Coulibaly, F., Verschoor, S., et al. (2010) · Nature · doi:10.1038/nature09518 · Cited by 435
Minoia, F., Davì, S., Horne, A., Demirkaya, E., Bovis, F., Li, C., Lehmberg, K., Weitzman, S. S., Insalaco, A., Wouters, C. H., et al. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38802 · Cited by 430
Self-citationHypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH
Zhang, K., Jordan, M. B., Marsh, R. A., Johnson, J. A., Kissell, D., Meller, J., Villanueva, J., Risma, K. A., Wei, Q., Klein, P. S., et al. (2011) · Blood · doi:10.1182/blood-2011-07-370148 · Cited by 428
Self-citationTo, K. K., Hung, I. F., Li, I. W. S., Lee, K., Koo, C., Yan, W., Liu, R. W., Ho, K., Chu, K., Watt, C., et al. (2010) · Clinical Infectious Diseases · doi:10.1086/650581 · Cited by 417
Ravelli, A., Magni‐Manzoni, S., Pistorio, A., Besana, C., Foti, T., Ruperto, N., Viola, S., & Martini, A. (2005) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2004.12.016 · Cited by 409
Cited by
Sorted by citations
Fajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196
Cytokine storms: understanding COVID-19
Mangalmurti, N., & Hunter, C. A. (2020) · Immunity · doi:10.1016/j.immuni.2020.06.017 · Cited by 698
COVID-19: Immunology and treatment options
Felsenstein, S., Herbert, J. A., McNamara, P. S., & Hedrich, C. M. (2020) · Clinical Immunology · doi:10.1016/j.clim.2020.108448 · Cited by 687
The Immunology of Macrophage Activation Syndrome
Crayne, C. B., Albeituni, S., Nichols, K. E., & Cron, R. Q. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00119 · Cited by 633
Self-citationOn the Alert for Cytokine Storm: Immunopathology in COVID ‐19
Henderson, L. A., Canna, S., Schulert, G. S., Volpi, S., Lee, P. Y., Kernan, K. F., Caricchio, R., Mahmud, S. A., Hazen, M. M., Halyabar, O., et al. (2020) · Arthritis & Rheumatology · doi:10.1002/art.41285 · Cited by 651
Self-citation
Metadata
- Authors
- Schulert, G. S., Zhang, M., Fall, N., Husami, A., Kissell, D., Hanosh, A., Zhang, K., Davis, K., Jentzen, J. M., Napolitano, L., Siddiqui, J., Smith, L. B., Harms, P. W., Grom, A. A., & Cron, R. Q.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- University of Alabama at Birmingham (US)
- University of Michigan (US)
- Corresponding author
- Cron, Randy Q.
- ORCID
- Venue
- Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-11-23
- Volume
- 213
- Issue
- 7
- Pages
- 1180-1188
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- PMC
- PMC4779301
- OpenAlex
- W2273799513
- Cited by
- 170
- References
- 52
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 14 · 2023: 15 · 2022: 15 · 2021: 25 · 2020: 42 · 2019: 15 · 2018: 9 · 2017: 13 · 2016: 3 · 2015: 1
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (R01-AR059049, K12-HL119986 to G. S. S.)
- the Kaul Pediatric Research Institute
- the American College of Rheumatology Rheumatology Research Foundation (scientist development award to G. S. S.)
- Topics
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- hemophagocytic lymphohistiocytosis, macrophage activation syndrome, H1N1 influenza, fatal influenza, NK cell cytotoxicity
- MeSH terms
- Female, Genotype, Humans, Influenza, Human, Killer Cells, Natural, Male, Mutation, Cohort Studies, Sequence Analysis, DNA, Genetic Predisposition to Disease, Lymphohistiocytosis, Hemophagocytic, Influenza A Virus, H1N1 Subtype, Perforin, Macrophage Activation Syndrome, HEK293 Cells, Exome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
