Relevant Research

The following is a short initial list of journal articles that we believe are relevant for parents and patients seeking information about Hyper IgM.

Research papers are listed in order of most recently published, and include study name, authors, date of publication, and abstract, as well as a short summary of what we thought was relevant. 

Hematopoietic stem cell transplantation for CD40 ligand deficiency: results from an EBMT/ESID-IEWP-SCETIDE-PIDTC Study (December 2018) 

Gennery AR, et al

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BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT).

OBJECTIVE: We performed an international collaborative study to improve patients’ management, aiming to individualize risk factors and determine optimal HSCT characteristics.

METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables relevance with respect to survival and cure.

RESULTS: Overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 78.2%, 58.1% and 72.3% 5 years post-HSCT. Results were better in transplants performed ≥2000 and in children <10 years old at HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT ≤2 years from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC) and bone marrow-derived stem cells. Most rejections occurred after reduced intensity or non-myeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was ≥50% donor in 85.2%.

CONCLUSION: HSCT is curative in CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS and DFS. Prospective studies are required to compare risks of HSCT with those of life-long supportive therapy.

Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation (September 2016)

De la Morena MT, et al

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Abstract: Background: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients.

Objectives: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT.

Methods: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression.

Results: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation.

Conclusion: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan (October 2015)

Kanako Mitsui-Sekinaka, MD,a Kohsuke Imai, MD, PhD,a,b Hiroki Sato, MS,c Daisuke Tomizawa, MD, PhD,b Michiko Kajiwara, MD, PhD,d Masayuki Nagasawa, MD, PhD,b Tomohiro Morio, MD, PhD,b and Shigeaki Nonoyama, MD, PhD. Saitama and Tokyo, Japan

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Abstract: Background: The long-term outcome of X-linked hyper-IgM syndrome (XHIM) caused by mutations in CD40LG is poor, and the only curative treatment is hematopoietic stem cell transplantation (HSCT). Objective: We sought to determine the clinical features and factors affecting outcomes in patients with XHIM. Methods We enrolled and retrospectively analyzed data from 56 Japanese patients with XHIM, including 29 patients who received HSCT. Results: The long-term survival rate was poor in those not undergoing HSCT (overall survival rate at 40 years of age, 28.2%). The overall survival rate of patients undergoing HSCT (n = 29) was significantly higher than that of those not undergoing HSCT (n = 27, P = .0231). Moreover, event-free and disease-free survival rates were significantly greater in patients 5 years old or younger at the time of transplantation (n = 14) than in older patients (n = 15). Conclusion: On the basis of these results, we concluded that HSCT improved the outcomes of patients with XHIM and that an age of 5 years or younger was optimal for the timing of HSCT because persistent infections and severe organ damage were frequently observed in patients older than 6 years.

Our Take: This is one of the more recent studies (March 2015) to come out that had a large sample size (as well as data from patients not included in most of the EU and US studies). A total of 54 patients were included in the study, 29 patients had received HSCT. The study showed similar results as many of the previous studies: (i) survival rate at 40 yrs is lower than 30%, (ii) HSCT was advised, and (iii) best results for HSCT are when the patients were 5 years or younger because of persistent infections and severe organ damage were frequently observed in patients older than 6 years.

First Report of the Hyper-IgM Syndrome Registry of the Latin American Society for Immunodeficiencies: Novel Mutations, Unique Infections, and Outcomes (Jan 2014)

Cabral-Marques O1, Klaver S, Schimke LF, Ascendino ÉH, Khan TA, Pereira PV, Falcai A, Vargas-Hernández A, Santos-Argumedo L, Bezrodnik L, Moreira I, Seminario G, Di Giovanni D, Raccio AG, Porras O, Weber CW, Ferreira JF, Tavares FS, de Carvalho E, Valente CF, Kuntze G, Galicchio M, King A, Rosário-Filho NA, Grota MB, dos Santos Vilela MM, Di Gesu RS, Lima S, de Souza Moura L, Talesnik E, Mansour E, Roxo-Junior P, Aldave JC, Goudouris E, Pinto-Mariz F, Berrón-Ruiz L, Staines-Boone T, Calderón WO, del Carmen Zarate-Hernández M, Grumach AS, Sorensen R, Durandy A, Torgerson TR, Carvalho BT, Espinosa-Rosales F, Ochs HD, Condino-Neto A.

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Abstract: Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.

Our Take: This is an important study as it is the first Hyper IgM study to come out the Registry of the Latin American Society for Immunodeficiencies. With a total of 58 patients, and published in 2014, like the Japanese paper, it has more recent data on a patients that have not been included in previous ones. Dr. Torgerson and Dr. Ohcs helped work on this one. I think the main takeaway from this study is that patients living in Central and South America are at greater risk of contracting certain opportunistic infections that are not common in the US and EU, and have not been identified in previous studies of Hyper IgM.

Immunoglobulin class switch recombination deficiency type 1 or CD40 ligand deficiency: from bedside to bench and back again (November 2013)

Hirbod-Mobarakeh A1, Aghamohammadi A, Rezaei N.

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Abstract: The immunoglobulin class switch recombination deficiency or hyper-IgM syndrome is characterized by normal or elevated serum IgM and low serum levels of other immunoglobulins. Since the first reported patient with hyper-IgM, more than 200 patients with this phenotype resulted from CD40 ligand deficiency have been reported. However, in addition to this common finding, they presented with different manifestations like opportunistic infections, autoimmunity and malignancies each of them are worth a detailed look. In this review, we will focus on different underlying mechanisms of these presentations to review what we have learned from our patients. In the end, we will discuss different treatment options available for these patients using this knowledge.

Our Take: This is an interesting study out of Iran from 2014, but not from a major journal. No new information or data here, but a good summary of many of the already published data on Hyper IgM. They combined all the previous data to get more than 200 patients (but does not include any recent (5-10 years) data). We find this study helpful for a few reasons: First, it has a really great references section at the end that basically includes 151 relevant published study on Hyper IgM before 2014. Second, it has a good summary of many of the co-morbidities relating to Hyper IgM as well as good explanations on the diagnosis and prognosis of disease. Lastly, it has one of our favorite lines from any study regarding Hyper IgM Patients, one that guides our foundation’s approach: “Effective management of CD40L deficiency requires a comprehensive individualized look to each patient regarding his/her course of disease and various manifestations. In this view, each efficiently managed patient is an individual piece of art.”

Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome (March 2005)

Lee WI1, Torgerson TR, Schumacher MJ, Yel L, Zhu Q, Ochs HD.

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Abstract: The hyper immunoglobulin M (IgM) syndrome (HIGM), characterized by recurrent infections, low serum IgG and IgA, normal or elevated IgM, and defective class switch recombination and somatic hypermutation, is a heterogenous disorder with at least 5 distinct molecular defects, including mutations of the genes coding for the CD40 ligand (CD40L) and IKK-gamma (NEMO) genes, both X-linked; and mutations of CD40, activation-induced cytidine deaminase (AICDA), and uracil-DNA glycosylase (UNG), associated with autosomal recessive HIGM syndromes. To investigate the molecular basis of HIGM, we determined the prevalence of mutations affecting these 5 genes in a cohort of 140 patients (130 males and 10 females). Those patients without a molecular diagnosis were subsequently evaluated for mutations of the following genes: inducible CO-stimulator molecule (ICOS), ICOS ligand (ICOSL), and if male, Bruton tyrosine kinase (Btk) and SLAM-associated protein (SAP/SH2D1A). We found mutations of CD40L in 98 males; AICDA in 4 patients (3 males, 1 female); UNG in one adult male; and Btk in 3 boys. Of the remaining 25 males, one infant with hypohidrotic ectodermal dysplasia had a mutation of NEMO. None of the remaining 33 patients (24 males/9 females) had mutations affecting CD40, ICOS, ICOSL, or SH2D1, and are best classified as common variable immune deficiency (CVID), although other genes, including some not yet identified, may be responsible.

Our Take: This study shows that the overall prevalence of CD40 Ligand Deficiency is approximately 70% of all Hyper IgM Syndrome cases.

The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients (November 2003)

Winkelstein JA1, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME.

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Abstract: The X-linked hyper-IgM (XHIGM) syndrome is an uncommon primary immunodeficiency disease caused by mutations in the gene for CD40 ligand and characterized by normal or elevated serum IgM, reduced levels of IgG and IgA, and defective T-cell function. Because of its rarity, it has been difficult for any single investigator or institution to develop a comprehensive clinical picture of this disorder. Accordingly, a national registry was developed in the United States to provide demographic, genetic, immunologic, and clinical information on a relatively large number of patients with the XHIGM syndrome.A total of 79 patients from 60 unrelated families were registered between January 1997 and July 2002. The estimated minimal incidence was approximately 1/1,030,000 live births. All of the patients had significant IgG deficiency and most had IgA deficiency, but only one-half had elevated IgM levels. Most patients presented initially with a history of an increased susceptibility to infection including Pneumocystis carinii pneumonia. The average age of diagnosis was significantly earlier in patients born into a family with a previously affected individual. However, only one-third of the patients born into a family with a previously affected individual were diagnosed exclusively because of the presence of the positive family history before any clinical symptoms developed. Over half the patients developed symptoms of immunodeficiency and were diagnosed by 1 year of age, and over 90% by 4 years of age. The most prominent clinical infections were pneumonia (81% of patients), upper respiratory infections (49%) including sinusitis (43%) and recurrent otitis (43%), recurrent/protracted diarrhea (34%), central nervous system infections (14%), sepsis (13%), cellulitis (13%), hepatitis (9%), and osteomyelitis (1%). In addition to infections caused by encapsulated bacteria, opportunistic infections were relatively common and were caused by P. carinii, members of the herpes virus family (including cytomegalovirus), Cryptosporidium, Cryptococcus, Candida, Histoplasma, and Bartonella. Sclerosing cholangitis occurred in 5 patients and in 4 of these was associated with Cryptosporidium infection. Eight patients had died at the time of their entry into the Registry; 2 of pneumonia (1 P. carinii and 1 cytomegalovirus), 2 of encephalitis (1 ECHO virus and 1 cytomegalovirus), 2 of malignancy (both hepatocellular carcinoma), 1 of sclerosing cholangitis caused by Cryptosporidium, and 1 of hemolytic uremic syndrome.

Our Take: This is the first large cohort paper on Hyper IgM Syndrome in the US, based on the original registry created for Hyper IgM Syndrome in 2002. These patients data would later be  moved into the USIDNET registry. As with Levy et al,  having a large cohort brings new insight to the overall clinical picture of the disorder as well as some insight into the prevalence.  Lower rates of Cryptosporidium were observed then the European study, but it is not clear if this is a result of better water supply or a difference in how the patients were ascertained in European data. Another key take away is that despite 28 of the 79 patients being born into families with a previous affected member, only 9 were diagnosed before developing an infection (like PCP/PJP). This emphasizes the importance of attention to positive family history in order to diagnose and treat before symptoms develop.

Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the European experience, 1993-2002 (February 2004)

Gennery AR1, Khawaja K, Veys P, Bredius RG, Notarangelo LD, Mazzolari E, Fischer A, Landais P, Cavazzana-Calvo M, Friedrich W, Fasth A, Wulffraat NM, Matthes-Martin S, Bensoussan D, Bordigoni P, Lange A, Pagliuca A, Andolina M, Cant AJ, Davies EG.

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Abstract: CD40 ligand (CD40L) deficiency causes recurrent sinopulmonary infection, Pneumocystis carinii pneumonia, and Cryptosporidium parvum infection. Approximately 40% to 50% of patients survive to the third decade: long-term survival is unclear. Hematopoietic stem cell transplantation (HSCT) is curative. We present a retrospective analysis of 38 European patients undergoing HSCT for CD40L deficiency in 8 European countries between 1993 and 2002. Donor stem cell source included 14 HLA-identical siblings, 22 unrelated donors, and 2 phenotypically matched parental stem cells (12 T-cell depleted). Of the patients, 34 engrafted and 26 (68%) survived; 3 had autologous reconstitution, 22 (58%) were cured, and 1 engrafted but has poor T-cell immune reconstitution. There were 18 evaluated patients who responded to vaccination. Of the patients, 12 (32%) died from infection-related complications, with severe cryptosporidiosis in 6. Grades 2 to 4 graft-versus-host disease (GvHD) associated with infection occurred in 6 of 12 fatal cases. HSCT cured 58% of patients, 72% of those without hepatic disease. Early T-cell function following whole marrow HSCT may limit cryptosporidial disease, but survival was similar after T-cell-depleted HSCT. Preexisting lung damage was the most important adverse risk factor. Further studies will determine optimal timing and type of HSCT.

Our Take: This is one of the more important studies that have been done on Hyper IgM, albeit, outdated (2004) and containing data from 1993-2002 from the European registries. This study includes 38 EU patients undergoing HSCT. Dr. Gennery is working on a follow up study that should cover the next 10 years or so and many more patients. As for outcomes, this older study shows similar life expectancy as some of the more recent ones. The HSCT outcomes have improved a lot since this data was collected. This is due to advances in HSCT, but also due to patients going into HSCT while still young and healthy as opposed to a last resort and when older.

Clinical spectrum of X-linked hyper-IgM syndrome (July 1997)

Jacov Levy, MD, Teresa Espanol-Boren, MD, Carolin Thomas, MD, Alain Fischer, MD, Pierangelo Tovo, MD, Pierre Bordigoni, MD, Igor Resnick, MD, Anders Fasth, MD, PhD, Maija Baer, MD, Lina Gomez, MD, E.A.M. Sanders, MD, Marie-Dominique Tabone, MD, Dominique Plantaz, MD, Amos Etzioni, MD, Virginia Monafo, MD, Mario Abinun, MD, Lennart Hammarstrom, MD, PhD, Tore Abrahamsen, MD, Allison Jones, MD, Adam Finn, MD, Timo Klemola, MD, Esther DeVries, MD, Ozden Sanal, MD, Manuel C. Peitsch, MD, Luigi D. Notarangelo, MD.

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Abstract: We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate.

Our Take: This is one of the first major studies and one of the most referenced for Hyper IgM. Conducted by Dr. Notarangelo and Dr. Levy it included 56 patient data collected from around Europe up until 1996. This study has only 3 patients who had HSCT as this is just starting to be an option to XHIM. This study only showed a 20% 25 year survival rate.


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