Background: Ataxia telangiectasia (AT) is a rare, multi-systemic, genetic disorder. Mutations in the ATM gene cause dysfunction in cell-cycle, apoptosis and V (D) J recombination leading to neurodegeneration, cellular, humoral immunodeficiencies and predisposition to malignancies. Previous studies have suggested that a sub-group of AT patients with elevated IgM levels have a distinct and more severe phenotype. In the current study we aimed to better characterize this group of patients. Methods: We performed a retrospective review of 46 patient records, followed from January 1986 to January 2015 at the Israeli National AT Center. Demographic, clinical, radiological, laboratory data was reviewed and compared between AT patients with elevated IgM levels (EIgM) and patients with normal IgM levels (NIgM). Results: 15/46(32.6%) patients had significantly elevated IgM levels. This group had a unique phenotype characterized mainly by increased risk of infection and early mortality. Colonization of lower respiratory tract with Mycobacterium gordonae and Pseudomonas aeruginosa as well as viral skin infections were more frequent in EIgM patients. Patients with NIgM had a significantly longer survival as compared to patients with EIgM but had an increased incidence of fatty liver or cirrhosis. T-cell recombination excision circles and kappa-deleting element recombination circle levels were significantly lower in the EIgM group, suggesting an abnormal class switching in this group. Conclusions: EIgM in AT patients are indicative of a more severe phenotype that probably results from a specific immune dysfunction. EIgM in AT should be considered a unique AT phenotype that may require different management. Keywords: AT, Class switching, Complications, Elevated IgM, Immunoglobulins, Lung functions, Phenotype Background Immunodeficiency is present in up to 70% of AT patients. Ataxia telangiectasia (AT) is a rare multi-systemic dis- Embryonic or absent thymus, premature ageing of the order. Mutations in the ATM gene causes dysfunction in immune system, abnormal T and B cell neogenesis and cell cycle, apoptosis, DNA repair and V (D) J recombin- abnormal surface T cell receptor expression were shown ation [1–3]. Neurodegeneration, predisposition to malig- to play a crucial role in AT associated immunodeficiency nancies as well as cellular and humoral immunodeficiency [2, 8]. The humoral immunodeficiency in AT includes are the main complications . Patients that have no IgG2 and IgG4 deficiencies, low or absent IgA and IgE ATM kinase activity are highly affected, while those with and abnormal humoral response to vaccination . Cellu- residual kinase activity usually present less severe neuro- lar immunodeficiency includes leukopenia, low CD4 + T logic disabilities and milder immune deficiency [5–7]. cell counts and impaired lymphoprolifirative responses to antigens and mitogens . AT patients often suffer from recurrent lower respiratory tract infections with subsequent * Correspondence: email@example.com pulmonary insufficiency resulting from a combination of Department of Pediatrics, The Edmond and Lily Safra Children’s Hospital, 52625 immunodeficiency, recurrent aspirations, decreased mobil- Tel- Hashomer, Israel Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel ization and abnormal muscle tone [3, 10, 11]. Poor growth, Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Krauthammer et al. BMC Pediatrics (2018) 18:185 Page 2 of 6 liver abnormalities and insulin resistant diabetes are also a Infections and immune function part of the AT phenotype [12–14]. We retrospectively reviewed all the available laboratory Several reports have suggested that a subgroup of data of the immune system from patient’s charts, including patients with AT present with higher levels of IgM that complete blood counts, immunoglobulin levels and distri- might be associated with a more severe phenotype bution, T-cell recombination excision circles (TREC) and [15–19]. A more recent study describing a cohort of kappa-deleting element recombination circle (KREC) levels 61 patients, concluded that patients with Hyper IgM as well as T and B cell subpopulations. Information regard- phenotype and IgG2 deficiency showed decreased sur- ing various infections was extracted from the patient’s vival compared to AT patients with NIgM . medical records and was further defined as viral, bacterial, The aim of the present study was to better fungal or parasitic. Quantification of TRECs and KRECs characterize the subgroup of AT patients with EIgM. We were determined by real-time quantitative (RQ)-PCR as hypothesized that patients with elevated IgM levels may was previously described [24, 25]. Age-matched healthy represent a separate phenotype similar to that seen in individuals were used as controls. Each experiment was Hyper IgM syndrome [21–23], leading to more severe performed in triplicate, and the threshold for Ct determin- infectious, neoplastic and pulmonary morbidity and ation was positioned at the same level each time. eventually shorter survival. Respiratory functions tests – Spirometry Methods In accordance with the AT clinic policy each patient had Patients spirometry tests results recorded at least once. Lung The Israeli National Clinical Center for Ataxia function measurements including forced vital capacity Telangiectasia at the Edmond and Lily Safra Children’s (FVC %) and forced expiratory volume (FEV 1%) were Hospital, Sheba Medical Center cares for most of the recorded, and the best of three results was included in Ataxia Telangiectasia patients in Israel. We retrospect- the study. ively reviewed the medical records of 53 AT patients followed at the Center between January 1st, 1986 and Serum liver enzyme levels January 31, 2015. Forty-six patients were enrolled in this Alanine transaminase (ALT) and aspartate aminotrans- study, and 7 were excluded due to lack of sufficient data. ferase (AST) levels were measured. Levels exceeding at The diagnosis of AT was based on a well-established set least 1.5 times the upper limit of normal (ULN) on 3 or of criteria, as previously published . Briefly, in more separate occasions were considered abnormal, addition to a distinctive clinical presentation suggestive after extensive workup to exclude possible etiologies for of AT one of the following was required: mutations in LFT elevation. the ATM gene, homozygous or compound heterozygous (N = 34), abnormal signal of the ATM protein on western Imaging studies blot (N = 12), or immune deficiency/chromosomal Chest X ray, abdominal sonography and other imaging breakage/T cell malignancy in the presence of increased studies were performed as part of the ongoing care of α-fetoprotein and cerebellar atrophy on magnetic reson- the patients. All radiographs were obtained with com- ance imaging (MRI) (N = 3). A specialized multidisciplin- puted radiography. All studies were evaluated by a ary team including an immunologist, pulmonologist and pediatric radiologists on a PACS workstation (Easyvision, gastroenterologist evaluated all the patients every Sectra Imtec AB, Linköping, Sweden) using Totuko 6 month, or more frequently if required. monitors (Totuko Electric co., ltd., Tokyo, Japan). Patients with IgM levels at least 20% higher than the upper normal limit (Additional file 1: Table S1), on at Statistical analysis least two separated occasions, were categorized as All measured variables and derived parameters were tab- “elevated IgM” (EIgM). Clinical characteristics, disease ulated by descriptive statistics. Pearson correlation coef- course and complications were compared between EIgM ficients were calculated for testing the relation between patients and patients with NIgM. Immune system func- two continuous parameters. Student’s T-test was applied tion, pulmonary function, infections, liver enzymes and for testing the statistical significance of the difference predisposition to cancer were analyzed and results were between means in continuous variables. All tests applied compared between the two groups. were two-tailed, and a p value of 5% or less was consid- The study was approved by the Sheba Medical Center ered statistically significant. Survival was assessed using Institutional review board (SMC-IRB). The data re- the Kaplan-Meier method. Differences in survival out- trieved from all patient charts was coded and de identi- comes were evaluated with the log-rank test. Statistical fied prior to analysis, hence the need for written consent analysis was done using the IBM ™SPSS™ Version 21 was formally waved by the SMC-IRB. software, New York, USA and Excel 2013 program. Krauthammer et al. BMC Pediatrics (2018) 18:185 Page 3 of 6 Results Human Papilloma virus skin infections were observed Medical charts of 46 AT patients (24 males), age in 2 out of 15 EIgM patients (13.3%) while none were seen 14.6 ± 4.6 years, were reviewed. The average age of AT in the 31 NIgM patients (p = 0.04). However, skin infec- diagnosis was 4.3 ± 3.6 years, and average duration of tions with HSV and VZV were similarly frequent in both follow-up was 8.3 ± 4 years (median 8 years, range groups (1/15 vs 0/31patients with HSV skin infections and 0.5–17 years). The diagnosis of AT was based on de- 2/15 vs 2/31 VZV infected patients, respectively). Systemic tection of ATM mutation in 35/46 (76%) of patients, infections with EBV and CMV were rare and were only low ATM on western blot in 9/46 (19.6%) and clinic- observed in 2 patients with NIgM. Herpes simplex virus ally in 2/46(4.4%) of patients. type 1 (HSV1) encephalitis and severe disseminated infec- Out of 46 patients with available IgM values, 15/46(33%) tion with Varicella zoster virus (VZV) were seen in one had EIgM with average serum IgM levels of 356 ± 200 mg/dl patient NIgM and one patient with EIgM. Skin infection that were statistically higher than the average IgM levels related to vaccinations were not observed. seen in the NIgM group (129.2 ± 56.5 mg/dl, p <0.001). Eight of 15 patients (53%) with EIgM, were males. There Pulmonary disease was no significant difference in average age between the In light of the higher frequency of chronic pulmonary infec- EIgM group and the NIgM group (15.2 ± 2.3 years vs tion in the EIgM group, we expected a more severe pattern 14.4 ± 5.1 years, p= 0.32, respectively). Clinical and of chronic pulmonary disease in this group. Information re- demographic characteristics of both groups are pre- garding pulmonary functions was available for 23/31(74%) sented in Table 1. patients with NIgM, aged 12.2 ± 5.4 years and 10/15(67%) of patients with EIgM, aged 12.2 ± 2.5 years, at the time of Complications observation. Average FEV1 and FVC measurements were Infections similar between the EIgM and NIgM groups 51.1 ± 20.1 vs During the follow-up period, 88 infectious episodes were 41.8 ± 10.6, p = 0.12 and 42.7 ± 15.3 vs 36.5 ± 7.8, p =0.13, documented in all patients. Bacterial infections were the respectively. During the follow up period, 329 chest X-ray most frequent 66/88 (75%), followed by fungal 12/88 examinations (CXR) were performed with an average of (13.6%), viral 9/88 (10.2%) and parasitic 1/88(1.2%) in- 1.2 ± 2.5 x-rays per patient per year of follow up in patients fections. AT patients suffered mainly from infections of with NIgM vs 1.1 ± 2.1 x-rays per patient per year of follow the respiratory tract, as was previously described [18–20]. up in patients with EIgM. All CXRs were re-evaluated by a Chronic pulmonary colonization with Mycobacterium gor- pediatric radiologist for the presence of bronchiectasis in donae and Pseudomonas aeruginosa were significantly both groups, however, no significant difference was found. more frequent in the EIgM patients than in patients with Bronchiectasis was present in 6 /31(19%) of the patients NIgM, 4/15(27%) vs 1/31(3%), p < 0.017 and 7/15(47%) vs with NIgM compared to 3/15(20%) of the patients in the 6/31(19.4%), p = 0.05, respectfully. The incidence of infec- EIgM group, p= 0.87. tions with Streptococcus pneumonia was similar in both groups. Colonization of the lower respiratory tract with Liver function tests (LFTs) Trichoderma sp., Candida sp. and Aspergillus niger LFTs were available in 41(89.1%) patients. There was no trended towards higher frequency in EIgM patients, but difference in the number of the EIgM and NIgM this trend did not reach statistical significance. patients with elevated LFT (9/13(69%) vs13/28(46.4%), respectively, p = 0.2). Neither average AST nor ALT were significantly different between the groups (49.8 ± 10.6 vs Table 1 Clinical characteristics of EIgM and NIgM patients 48.1 ± 27.8 IU/L, p= 0.4 and 33.7 ± 10 vs 47.2 ± 32.7 IU/L, Parameter EIgM NIgM p p = 0.08, respectively). Abdominal sonography was per- N 15/46(32.6) 31/46(67.4) N/A formed in 14/15 (93.3%) patients with EIgM and 26/ 31(84%) with NIgM). Interestingly, none of the EIgM Gender, male 8/15(53) 16/31(52) p= 0.9 patients developed signs of fatty liver or cirrhosis, Average age, years 15.2 ± 2.8 14.3 ± 5.2 p= 0.35 while 9 of the 26 (34.6%) patients with NIgM levels Age of elevated IgM 9.3 ± 4.2 N/A N/A showed these liver abnormalities, p < 0.01. Average detection, years alpha-fetoprotein (AFP) levels were similarly elevated IgM levels (mg/dl) 356 ± 200 129.2 ± 56.5 p < 0.001 in both groups (286.5 ± 198 ng/ml in EIgM patients Deceased N/Total in 8/15(53.3) 9/31(29) p = 0.05 vs 251 ± 157 ng/ml in NIgM patients, p = 0.55). the group Age at demise, years 13.7 ± 4.2 18.3 ± 6.3 p = 0.042 Cancer N/A Not Applicable a Cancer remained one of the main complications and lead- Continuous variables are presented as mean ± SD. Categorical variables are presented as N (%) ing causes of death among our patients. Three of 15 (20%) Krauthammer et al. BMC Pediatrics (2018) 18:185 Page 4 of 6 EIgM patients had cancer compared to 9 of 31(29%) pa- in our cohort. The baseline evaluation included complete tients with NIgM, p= 0.5. Lymphoma, acute lympho- blood count, immunoglobulin levels, T, B lymphocyte and blastic leukemia all of them T-cell (T-ALL) and solid NK cell sub-populations and basic complement studies. tumors were the leading cancers seen in our cohort CD20+ lymphocytes and CD3+ lymphocytes were de- (8/46(17.4%), 4/46(8.7%) and 5/46(10.9%), respectively). creased in 8/46(17.4%) and 15/46(32.6%) of the patients, These findings are similar to those reported in previously respectively, while 7/32(21.9%) of the patients had reduced published cohorts [12, 26]. The average age of cancer lymphoproliferative responses. We did not observe any diagnosis was 10.7 ± 3.3 years in the EIgM group vs significant difference in lymphocyte subpopulations and 11.2 ± 6.2 years, in the NIgM patients. Several patients lymphoproliferative responses between EIgM and NIgM were diagnosed with more than one type of cancer. patients. There was no significant difference in comple- ment levels or in the ability to mount an adequate re- Mortality and survival analysis sponse to vaccination (data not shown). During the 29 years of follow up 17(37%) patients died. The need for immunoglobulin replacement therapy with The average age of death was 15.4 ± 6.3 for the entire co- IVIG trended to be more frequent in the group of patients hort. The oldest patient alive at the time of the end of the with EIgM in which 10/13(77%) received IVIG as com- study was 25.1 years old. The longest survival observed pared to 14/27(52%), (p= 0.13) in the NIgM group. was 27.1 years. These results are similar to the survival ob- Previous studies on this cohort of patients have dem- served in previously published cohorts [20, 26]. Patients onstrated that AT patients have low T-cell recombin- with NIgM levels had significantly longer survival com- ation excision circles (TREC) and kappa-deleting pared to patients with EIgM (z = 2.31, p = 0.05) (Fig. 1). element recombination circle (KREC) levels with abnor- The average age of death was 13.4 ± 4.2 years for the EIgM mal TCR-Vβ repertoires . group vs 18.3 ± 6.3 years, (p= 0.042) in the NIgM patients. Interestingly, despite the similar amounts of CD3+ and CD20+ cells in both groups, we observed a signifi- Immunologic findings cantly lower KREK-CJ and TREK levels and a trend As part of the routine follow-up of AT patients, a broad towards lower KREK-SJ levels in the EIgM group com- immunological evaluation was performed in most patients pared to the levels in normal IgM patients (Table 2). Table 2 Immunological features of EIgM and NIgM patients Parameter EIgM NIgM p N =15 N =31 WBC (K/mL) 8.8 ± 1.6 8 ± 2.9 p = 0.16 ANC (K/ml) 5.6 ± 1.3 5.2 ± 2.5 p = 0.3 ALC (K/ml) 1.7 ± 0.5 1.9 ± 0.8 p = 0.25 CD3 + (K/ml) 1042 ± 526 959 ± 511 p = 0.33 CD4 + (K/ml) 466 ± 236 839 ± 1797 p = 0.25 CD8 + (K/ml) 597 ± 433 443 ± 247 p = 0.09 CD20 + (K/ml) 145 ± 67 167 ± 185 p = 0.36 CD56+ (K/ml) 26 ± 10 23 ± 10.7 p = 0.24 Patients treated with IVIG 10/13(77) 14/27(52) p = 0.13 Age at IVIG initiation (years) 9.4 ± 5.7 6.6 ± 3.7 p = 0.09 Average IgA (mg/dL) 82 ± 97 59.5 ± 81 p = 0.22 C3(mg/dL) 146 ± 30.4 144.1 ± 11.3 p = 0.46 C4(mg/dL) 27 ± 8 37.4 ± 1.8 p = 0.06 KREC-CJ 732 ± 390 2568 ± 3115 p = 0.033 KREC-SJ 22 ± 17 112 ± 199 p = 0.08 TREC 13.9 ± 8.2 64.2 ± 93.5 p = 0.046 Fig. 1 Kaplan-Meier curves for mortality in patients with NIgM levels and patients with EIgM. EIgM was associated with significantly Normal lymphocyte proliferation 6/9(67) 19/23(83) p = 0.33 increased mortality risk when using Log-Rank test to compare the 2 WBC white blood cells, ANC Absolute neutrophil count, ALC absolute groups (z = 2.31, p = 0.05). The data is presented as the percent of lymphocyte count, IVIg Intravenous immune globulin, C Complement, patients alive at each age. The survival data is presented only for the NK Natural Killer cell, TREC T cell receptor excision circle, KREC kappa-deleting recombination excision circles (CJ ψJα coding joint, SJ ψJα signal joint) first 20 years of life since only 7 patients from NIgM group and none of Continuous variables are presented as mean ± SD. Categorical variables are the EIgM group over 20 years of age were included in the study presented as N (%) Krauthammer et al. BMC Pediatrics (2018) 18:185 Page 5 of 6 Discussion Conclusions AT is a rare, autosomal recessive, progressive, multi sys- Taken together, our findings further support previous re- temic disease with well described cellular and humoral ports suggesting that AT patients with elevated IgM immunodeficiency . Hypogammaglobulinemia with levels represent a distinct group with a severe disease low IgG, IgA and IgE levels, is a frequent presentation of phenotype and worse prognosis resulting from a prom- this disease . On the other hand, different studies inent CSR defect. have shown variability in IgM levels in these patients Further larger prospective studies in this subpopula- with normal or mildly elevated levels in up to 60% of the tion would be needed to establish a tailored manage- patients . As a result, some AT patients are initially ment approach including close surveillance with early misdiagnosed with Hyper IgM syndrome, while the de- and aggressive treatment. finitive AT diagnosis is made later by genetic analysis or western blot, following the accumulation of clinical char- Additional file acteristics indicative of AT. Recent studies advocated that elevated IgM levels should be included in the diag- Additional file 1: Table S1. The reference range of immunoglobulin nostic criteria for AT suggesting that patients with this M (IgM) based on age*. (DOCX 13 kb) presentation might have a worse prognosis [19, 20]. In our cohort, 15 of 46 patients (32.6%) had elevated Abbreviations IgM levels, a slightly higher fraction as compared to pre- AFP: Alfa fetoprotein; AT: Ataxia telangiectasia; ATM: Ataxia telangiectasia mutated; BMI: body mass index; CMV: Cytomegalovirus; CSR: Class switch viously published cohorts [19, 20, 28]. recombination; EBV: Epstein-Barr virus; EIgM: Elevated IgM; FEV1: Forced We have observed that AT patients with elevated IgM expiratory volume (1 sec); FVC: Forced vital capacity; HSV1: Herpes simplex levels are more prone to colonization of the lower respira- virus type 1; IgM: Immunoglobulin M; IVIG: Intravenous immunoglobulin; KREC: Kappa recombination excision circles; NASH: Nonalcoholic tory tract with pathogenic gram-negative bacteria as well as steatohepatitis; NIgM: Normal IgM; NK: Natural killer cells; PEG: Percutaneous to higher frequency of viral skin infections, a presentation gastrostomy; TCR: T cell receptor; TREC: T-cell receptor excision circles; similar to that seen in other Hyper IgM phenotypes . VZV: Varicella zoster virus Despite these findings, we were not able to demon- strate a significant difference in pulmonary function be- Availability of data and materials The datasets used and analyzed during the current study are available from tween AT patients with normal or elevated IgM levels. the corresponding author on reasonable request. This may have resulted from the fact that lung function testing in our cohort was done at a relatively young age, Authors’ contributions before recurrent lung infections had inflicted significant AK conceptualized and designed the study, drafted the initial manuscript, accumulative damage to the lung tissue. and approved the final manuscript as submitted. AL, LG, BW, IS, RS and MS carried out the initial analyses, reviewed and revised the manuscript. IMP Predisposition of AT patients to hepatic disease, which in designed the data collection instruments, coordinated and supervised data some cases progresses to non-alcoholic steatohepatitis collection and critically reviewed the manuscript. All authors edited and (NASH) and even cirrhosis with portal hypertension, was re- approved the final manuscript as submitted. cently described . In the current study, we observed that patients with elevated IgM levels did not present this pheno- Ethics approval and consent to participate The above study was reviewed and approved by the Sheba Medical Center type. The progression of liver disease and insulin resistance Institutional review board (SMC-IRB), (reference 2867–15-SMC). The data in AT patients were recently shown to be age dependent retrieved from all patient charts was coded and de identified prior to . Thus, it is possible that the shortened survival in the analysis. Since this study is a retrospective chart review study the need for written consent was formally waved by the SMC-IRB. EIgM group paradoxically results in less apparent liver in- volvement, which might have developed, should these pa- Competing interests tients have survived longer. On the other hand, this could The authors declare that they have no competing interests. also be a distinctive clinical characteristic of the EIgM group. Further studies are needed to better illuminate this question. Increased risk of developing cancer is a well-known Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in feature of AT [12, 26, 31]. In contrast to previous re- published maps and institutional affiliations. ports, we did not observe an increased risk of malig- nancy in the group of EIgM patients. Author details Department of Pediatrics, The Edmond and Lily Safra Children’s Hospital, 52625 Recent studies have investigated class switch recom- Tel- Hashomer, Israel. Pediatric Gastroenterology Unit, The Edmond and Lily bination (CSR) as a critical mechanism in lymphocyte 3 Safra Children’s Hospital, Tel- Hashomer, Israel. Pediatric Pulmonary Unit, The maturation in AT, reporting abnormal class switching in Edmond and Lily Safra Children’s Hospital, Tel- Hashomer, Israel. Pediatric Radiology Unit, The Edmond and Lily Safra Children’s Hospital, Tel- Hashomer, AT patients with high IgM levels [20, 28, 32]. The lower Israel. The Claudio Cohen Department of Pediatric Intensive Care, The Edmond levels of KREC and TREC levels seen in the EIgM group 6 and Lily Safra Children’s Hospital, Tel- Hashomer, Israel. Sackler Faculty of in our cohort further supports these findings. Medicine, Tel-Aviv University, Tel-Aviv, Israel. Krauthammer et al. 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BMC Pediatrics – Springer Journals
Published: Jun 4, 2018
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