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EXPERIENCE IN TREATING CHILDREN WITH PRIMARY COMBINED IMMUNE DEFICIENCIES AND THEIR SURVIVAL IN CONDITIONS IN UKRAINE

L.V. Kostiuchenko, L.І.Chernyshova, Ya.Yu. Romanyshyn, І.Ya. Savchak
Western_Ukrainian Specialised Children Medical Centre, Lviv P. L. Shupik National Medical Academy of Postgraduate Education, Kyiv


The work presents the first ever experience in, and results of observing and treating children with various combined immune deficiency (CID) forms in Ukraine. The observation involved 121 children with various CID forms. High mortality in children with CID and possibilities of their survival with well-timed application of adequate therapy is shown. The work also presents revised approaches towards substitution therapy with immunoglobulins, antibiotic therapy and prevention measures at various CID forms as well as indications for stem cell transplantation.
Keywords: primary combined immunodeficiencies, complex combined immunodeficiencies, Nijmegen breakage syndrome, Wiskott-Aldrich syndrome, Louis Barr syndrome, DiGeorge syndrome, stem cell transplantation, intravenous immunoglobulins.



Introduction

Primary combined immunodeficiencies (CID) are a heterogeneous group of genetically determined disorders characterised by T and B cell dysfunction frequently associated with reduced T cell counts and immunoglobulin levels and other congenital abnormalities. CIDs lead to atypically high and grave morbidity from various infections, autoimmune phenomena and liability to oncological pathologies. CIDs occupy an important place in children abnormalities as they are often the cause of high morbidity, incapacitation and mortality in children with that pathology [1].

It's only in the past 10 to 15 years that it has become possible to develop this area in Ukraine owing to implementation of modern immunological diagnostic techniques and use of molecular genetic diagnose verification by national and international labs. In the last years there have been certain improvements in CID diagnostics in children which, however, have not led to full detection of disease cases yet. Late diagnoses and the lack of adequate therapeutic follow-up of children with CID bring about high children mortality and disability rates and a low level of population replacement [2].

With a view of permanent congenital immune system defect, patients with CID require a lifelong medical attention. Treatment envisions a comprehensive approach with proper account for defect gravity, the need for and possibility of its correction, and treatment and prevention of infections (as the main clinical syndrome) and other associated conditions.

Radical methods of CID treatment aim at elimination of the existing immune system defect with such intents-to-treat as stem cell transplanting (SCT) or gene therapy. Diagnosing a grave combined immune deficiency (SCID) makes the absolute indication for SCT because of 100% lethality of such cases in the event of the disease left to progress naturally. According to European research centres, SCT administration at SCID with stem cells taken from an HLA-i-dentical donor provides for survivability of more than 95% patients [5, 11]. In conditions of Ukraine, an SCT from a donor outside the patient's family is impossible due to the absence of access to international bone marrow data banks and the experience of SCT from a donor in the family is still limited to the treatment of onco-haematological patients. In other words, extra administration issues and considerable time necessary for searches for a clinic abroad and for sufficient funds to pay for the treatment etc. make additional hindrances to SCT administration to our patients.

The work presents the first experience in observing and treating children with different CID forms and their results.

Work objective: to assess performance of the existing treatment methods and their effect on survivability of patients with various nosological primary CID forms.


Research Material and Methods

121 children aged between ten days and 18 years with various CID forms were observed; of those, 22 children with grave combined immune deficiency (-SCID); 29 patients with ataxia telangiectasia (АТ); 32 patients with Nijmegen breakage syndrome (NBS); 8 patients with Wiskott-Aldrich syndrome (WAS); and 26 patients with DiGeorge syndrome (DGS). Another group comprised children with rare CID forms, of these two were with Netherton syndrome, one with X-linked lymphoproliferative disease and another one, with idiopathic CD4+ lymphocytopenia (Table). Retrospective and prospective studies of patients' morbidity and the assessment of therapeutic regimen applied and life time of the patients were carried out. Generally accepted clinical and lab screening tests were used, among them flow cytometry to determine key lymphocyte populations and subpopulations and nephelometry or EIA, to determine Ig A, M, G, Е antibody serum levels. CID diagnoses were conclusively confirmed based on molecular genetic tests: sequencing of WAS, RAG1, RAG2, Artemis, ADA and IL-2RG genes (responsible for development of the most frequent SCID forms); determination of the «Slavic» NBN mutation and the six most widespread ATM mutations using the PCR method; and determination of 22q11.2 microdeletions using the FISH-technique (for DGS).

The obtained results were processed using the Statistica for Windows 5.0 software. For the purpose of assessment of general survivability index KaplanMeir survival curves with determination of median, lower and higher survival quartiles were used. Groups were compared using the logrank test.




Research Results and Their Discussion

Patients with combined immune deficiencies and, particularly, with SCID, NBS, AT and WAS suffer from severe recurrent infections of diverse aetiology and localisation that, if inadequately treated, lead to substantial dysfunctions in affected organs, quick chronisation of niduses of infection and ultimately, threaten the very life of the patient. Many nosological CID forms, excluding the infection syndrome, also cause other serious problems like CNS injury at NBS and AT, hemapoiesis disorder at WAS, cardiovascular malformations, palate defects at DGS, high liability to oncological pathologies at NBS and AT etc. depending on CID variant and gravity of the disease. High mortality rates among patients with CID requires in some cases definitive therapeutic measures like haematopoietic stem cell transplantation or gene therapy or, in some patients, may be limited to non-surgical follow-up medical support.

Bone-marrow (SCT) was transplanted to five patients with CID; of those, two had SCID and the remaining three, WAS. SCT was carried out in the hospital in Brescia, Italy, with funds from the Lifeline International Charitable Foundation for which we are extremely grateful to it. One of the patients with WAS died three months after the SCT because of post-transplant surgery complications (severe graft vs. host disease and infectious complications that progressed extremely rapidly on the background of immunosuppressive therapy). The four patients who survived and returned to Ukraine after a successful SCT were: two children with SCID (АDА deficit and Х-linked SCID) and another two, with WAS. One child with RAG1 deficit died during the SCT preparation phase because of severe infectious complications (BCG infection,
salmonellosis; later on, an unidentified neural infection that became the cause o death). Two (9.1%) of all the patients with SCID received SCT treatment. All other SCID patients who were not administered SCT died.

The majority of the children died before reaching 18 months of age and only two of them who had SCT (9.1% from the total number of patients with SCID) survived. The median survival was at 0.73 year, from 0.01 to 4 years, and the lower and the higher quartiles made 0.2 and 1.2 years, respectively. Total mortality rate in this group of patients for the duration of observation reached 90.9%. That way, SCT is the only efficient way of treating SCID patients able to assure survival of the patient if timely administered. SCT is also the principal treatment for WAS patients: it allows simultaneously eliminating all haemopoiesis disruptions and restoring immune functions as is efficient in 70% cases. SCT risks are related to high lethality from intercurrent infections, the graft vs. host disease, graft rejection and post-transplant lymphoproliferative disorder [6, 7, 9]. With a view of that, studies into gene therapy of the Wiskott—Aldrich syndrome are being held; the studies are at this stage past all pre-clinical phases and open for recruitment of patients [13]. With the disease progressing naturally, the average life expectancy for WAS patients is from eight to 20 years [3]. For the cohort of WAS patients in our research, the total mortality for the duration of the observation reached 25%. The age that the patients under observation reached was: median — 6.5 years, from two to 22 years; the lower and the higher quartiles were 3.5 and 11.25 years, respectively. The death causes were: infectious complications (50% of the deceased) and CNS haemorrhages (50% of the deceased). Of the three patients who were administered SCT, one died of complications. A decision on definitive treatment is taken in each WAS case individually based of the severity of disease progress, availability of family donor and the patient's age.

For patients with NBS, AT and DGS no possibility of immunorestorative interventions has been considered because of little available international experience of such interventions for the mentioned diagnoses and their impracticality for the absolute majority of patients with the above CID forms. Such patients are administered conservative treatment aimed at prevention and therapy of infectious complications, correction of congenital malformations (for DGS) and treatment of oncopathologies (for NBS and AT).

Regular substitution therapy with immunoglobulin products (IVIG) administered in accordance with indications either for life or until antibody production function restoration after definitive treatment is another yet important way of CID mitigation. As not all CID forms are accompanied with a reduction of serum immunoglobulin levels, the extent of antibody production function loss may considerably differ from one patient to another and show age-related changes in one and the same patient even within one and the same nosological CID form.
IVIG treatment was administered to 54 (51.9%) children, of them 10 with SCID, 21 with NBS, eight with АТ, another eight with WAS, and five children, with DGS. Some of the patients received IVIG on a regular basis as substitution therapy; other children received the drug irregularly because of issues with provision of medicines. On a number of occasions IVIG was administered from time to time due to either severe acute infection or preparing children with DGS for cardiac or palate surgery. The duration of continued treatment with IVIG products ranged between three months and five years; the dosage was from 400 to 800 mg/kg every four weeks.

Of all the SCID patients, 10 (45.4%) received IVIG; of those, six children were on regular substitution therapy with doses from 600 to 800 mg/kg from the moment of diagnosis. Of them, two were sent for SCT and survived; four patients died. Another four were administered occasional IVIG infusions (from one to three) for the duration of treatment of grave infections; we did not analyse these infusions as replacement therapy. The survival time of patients with SCID who received IVIG substitution therapy resulted to be considerably longer than that of those who did not receive it (р<0.01; Cox's F criterion, Pic. 1).



The efficacy of IVIG substitution therapy in patients with NBS was accessed in 11 patients who received IVIG regularly and was found to depend on the timeliness of its administration. Good clinical effect conditioned by early disease detection and timely commencement of substitution therapy before chronic infection niduses were formed was found in six (54.5%) patients; these children had no invasive infection forms (like otitis or pneumonia) and their RI morbidity was within the range of two to three cases a year. The IVIG therapy was of little effect in two cases of late diagnosis (when it was not possible to secure sanitation of chronic niduses); also it was found ineffective for prevention of oncological complications in patients with NBS.

The IVIG therapy was regularly administered to five patients with АТ (17.2%). Four more children who had no indications for a regular substitution therapy received occasional IVIG infusions during acute infections (pneumonia) both as treatment measure and to prevent chronic infection niduses from forming. The effectiveness of the substitution therapy was assessed in five patients who received IVIG for six months at least. In two of them (40% of the number of patients treated with IVIG) demonstrated a good effect in the form of stabilisation of bronchopulmonary process conditioned with substitution therapy administration at the early stage of chronic infectious nidus formation. As it was not possible to attain sanitation of the infectious niduses in other three patients with long-lasting anamnesis of chronic bronchitis and sinusitis, they were administered, beside the substitution therapy, also long-term continuous antibiotic treatment. The measures failed to bring the desired effect: the patients showed further progress of chronic bronchopulmonary process on the background of progredient cerebral degeneration and eventually all three died in the age of eight, nine and 12.7 years, respectively irrespective of maximum efforts to treat infectious complications taken.

Regular substitution therapy with IVIG was administered to four (50%) patients with WAS while another four patients received occasional infusions for acute invasive infections or aggravations of chronic infectious niduses. Decisions on IVIG administration for such patients depended not on their IgG blood levels but rather on the severity of infection syndrome and social considerations (problems with treatment provision). Two patients treated with SCT received high-dosage IVIG treatment (0.8 g/kg every three weeks) during the pre-grafting and post-grafting period. A positive effect was noted in cases of regular treatment: a regression of the infection syndrome in absence of severe bacterial infections, specifically pneumonias, otitis etc.; however, the administration of substitution therapy had no effect on the progression of CMV infection.

Among all the DGS patients only six (23.1%) necessitated IVIG therapy, of them four only occasionally (for treatment of pneumonias and during massive surgeries) and two more as a substitution therapy carried out simultaneously with preventive antibiotic treatment for an evident infection syndrome. Like with WAS, the IgG blood titre was not the determinant factor in the making of decision on the commencement of substitution therapy. Two infant patients with low IgG (<2 g/l) titres received IVIG during preparations for surgeries and further on, in relation with IgG level restoration to normal and in absence of the infection syndrome without further need of immunoglobulin injections. The tactics of occasional IVIG administration at massive surgeries have been proven true during the study with a view that the four patients with DGS (30.8%) who had been surgically treated for congenital heart diseases had severe bronchitis and pneumonias/pleuropneumonias during the postsurgery period, which was not the case in patients who underwent surgeries after IVIG treatment.

While no statistically meaningful prolongation of survival period due to IVIG therapy administration was proven to exist for patients with WAS, NBS, AT and DGS, the said therapy did show clinical efficacy in the majority of patients with the mentioned CID forms provided its timely administration.

Antibiotic therapy is considered part and parcel of the CID therapy administered not only with infections present but also as an antimicrobial prevention measure [10–12]. The results of our work demonstrated extremely high relevance of antibiotic therapy for CID patients and the importance of causative agent identification for the success of the therapy with a view of the great importance of causative agents not sensitive to generic antimicrobial products for aetiology of viral, fungal and pneumocystal infections, BCG vaccine strain bacteria activation etc. During the treatment of infections or relapsing chronic niduses long-term, high-dosage therapy was administered with due regard to sensitivity of identified causative agents. Treatment of patients with SCID posed the most problems as a considerable proportion of them, even with highly aggressive antibiotic course administered, would not show any stable improvement of condition and die of progressive infectious diseases. Therapy of infectious complications in SCID requires a highly aggressive antimicrobial treatment, often involving rescue medications, prolonged treatment regimens and proper regard to aetiological infection particularities SCID (pneumocystosis, BCG infection, CMV etc.) that require specific therapy in SCID. International professionals follow a similar tactics [4, 10, 12].

36.4% of SCID patients in whom a remission of infectious niduses was achieved were further administered preventive antimicrobial therapy: trimethoprim-sulfamethoxazole (TMP/SMX), fluconazole, and acyclovir. The preventive antimicrobial therapy substantially (р<0.005) increased life expectancy for SCID patients compared with patients from the same group who did not receive such treatment (Pic. 2, 3). High complication prevalence rates after BCG vaccination (36.4%) observed in this group of patients also conditions the need for preventive administration of two or three tuberculostatics similar to practices adopted in other countries with injection schedules envisioning early BCG vaccination [10]. Secondary prevention of BCG infection was administered to three (13.6%) of our patients.




The majority of patients with other CID forms also received antibiotic therapy, both occasionally for treatment of infections (86.2% to 100% patients depending on nosology) and, in some cases, simultaneously with antifungal medications (48.3–100%). Recurrent infections required long-time administration of antibiotics, in some cases several courses in a row with product changes to match sensitivity of the singled-out flora (-that also included the use of rescue medications). Patients with frequently recurring and chronic respiratory infections (from 15.4% patients with DGS to 75%, with WAS) were administered long-term or continuous preventive antibiotic therapy with TMP/SMX or broad-spectrum antibiotics to sanitise infectious niduses and prevent their further exacerbations.

Some of the patients with oncological complications of NBS and АТ received polychemotherapy for lymphomas, and only 33% patients survived. This already low five-year survival rate is much lower than that reachable with modern methods of treating of non-Hodgkin lymphomas in children: 87.7% in 2000 to 2004 with forecasted 90+% after 2005. This shows the need for implementation of special treatment regimens for patients with increased chromosome fragility the efficacy of which has already been proved abroad [8, 14].

High mortality was registered in the cohort of NBS patients. The total mortality for the duration of the observation reached 25%. The age reached by the patients under observation was: median: 6.5 years (from 0.1 years to 22 years); lower and higher quartiles: 5.3 and 10.3 years, respectively. The causes of death were: oncological complications (75% all the deceased) and progressing chronic bronchopulmonary infection process (25% of the deceased). The assessment of the survival time of the patients with NBS who were administered IVIG substitution therapy and preventive antibacterial therapy showed no significant difference from the patients that did not receive these therapies (р>0.01; Cox's F criterion). This can be explained with the fact that the administration of the mentioned therapy measures are indicated for those NBS patients with certainly more severe disease progress and respectively, shorter life span when other patients with less severe progress have no such need in these medications and enjoy a more optimistic life expectancy prognosis.

Similar treatment results were obtained in the group of AT patients: in it, the total mortality during the time of observation was at 27.6%. The age reached by the patients under observation was: median: 11 years (from 2 years to 25 years); lower and higher quartiles: 8 and 13.5 years, respectively. The causes of death were: oncological complications (37.5% of the deceased) and progressing chronic bronchopulmonary infection process (62.5% of the deceased).

The lowest mortality levels were found in the group of patients with DGS: the total mortality for the observation period was at 11.5%. The age reached by the patients under observation was: median: 1.62 years (from 0.1 years to 18 years); lower and higher quartiles: 1 and 3.5 years, respectively. For DGS, the mortality peaks in the first and second years of the life of patients. The causes of death were: infectious complications (33.3% of the deceased) and decompensation of severe incurable cardiovascular diseases
(66.6% of the deceased).

The studies of efficiency of the existing treatment regimens for children with CID attest to dependence of therapy's end results from the timelines of diagnosis and level of severity of the disease. Early CID diagnosing and choosing therapeutic tactics, particularly, in cases when definitive treatment is necessary can give such patients a chance to live — and even to recover (-with SCT). While we did not succeed in providing a statistical proof of life time dependence on IVIG substitution therapy and preventive antibiotic therapy administration for NBS, АТ and DGS, nevertheless the mentioned tactics is justified from the standpoint of potentially reachable long-term remissions and improved quality of life of many patients with CID and is widely used for practical treatment of such patients.


Conclusions


1. SCT is a highly efficient method of correcting grave CID forms like SCID and WAS. However, the main prerequisite for the success of such intervention lies in early diagnosis of disease, expedite donor screening and adequate, highly aggressive anti-infection therapy at preparing for SCT and in the post-grafting period.

2. Presence of severe hypogammaglobulinemia in a patient with CID is the absolute indication in favour of regular substitution therapy administration. Substitution therapy with IVIG is indicated also to patients with satisfactory IgG titres in cases of expressed progressing infection syndrome and/or acute severely progressing infections. In the latter case IVIG may be administered on an occasional basis as a treatment measure aimed at infection elimination in parallel with causal treatment.

3. Antibacterial therapy is an important component of treatment of CID patients. It is administered based on expanded indications and with highly aggressive methods both to eliminate infection niduses and indication-wise, to prevent further complications.

4. Patients with SCID do need continuous antibiotic-based prevention of infections and IVIG substitution therapy: these considerably prolong their life expectancy and provide possibilities of preparing for stem cell transplantation.


References

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  2. Chernishova L.I. Problemi i dosyagnennya dityachoi klinichnoi imunologyi v Ukraini u 2006 rotcy. Perynatol. i pediatriya. 2007; No. 3 (31): 5—6.
  3. Sullivan K.E., Mullen C.A., Blaese R.M., Winkelstein J.A. A multiinstitutional survey of the Wiskott—Aldrich syndrome. J. Pediatr. 1994; 125 (6 Pt 1): 876—885.
  4. ASHP therapeutic guidelines for nonsurgical antimicrobial prophylaxis / American society of health system pharmacists. Am. J. Health Syst. Pharm. 1999; 56, No.12: 1201—1250.
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  7. Antoine C., M?ller S., Cant A. [et al.] Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968—99. Lancet. 2003; 361(9357): 553—560.
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  9. Kobayashi R., Ariga T., Nonoyama S. [et al.] Outcome in patients with Wiskott—Aldrich syndrome following stem cell transplantation: an analysis of 57 patients in Japan. Br. J. Haematol. 2006; 135(3): 362—366.
  10. Bernatowska E., Wolska-Kusnierz B., Pac M. [et al.] Risk of BCG infection in primary immunodeficiency children. Proposal of diagnostic, prophylactic and therapeutic guidelines for disseminated BCG based on experience in the Department of Immunology Children's Memorial Health Institute in Warsaw between 1980—2006. Centr Eur J. Immunol. 2007; 32, No. 4: 221—225.
  11. Small T.N., Friedrich W., O'Reilly R.J. Hematopoietic Cell Transplantation. Hematopoietic Cell Transplantation for Immunodeficiency Diseases; Thomas E. D., Blume K. G., Forman S. J. (eds). — Oxford : Wiley-Blackwell, 2009: 1105—1124.
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МедЭксперт. Медицинские статьи. Медицина, лечение, здоровье
    
Опубликовано: 2013/5/15 15:50:35 2771

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» EFFECT OF DOMESTIC MULTI PROBIOTIC ON ACUTE RESPIRATORY DISEASE MORBIDITY RATES AND PSYCHOMOTOR DEVELOPMENT INDEX IN ORPHANS FROM CHILDREN'S HOME
» COMPARATIVE EVALUATION OF EFFICACY OF VARIOUS SYMBITER MULTI PROBIOTIC PREVENTIVE INTAKE REGIMENS IN DOUBLE BLIND PLACEBO-CONTROLLED TRIAL IN CHILDREN
» EXPERIENCE IN TREATING CHILDREN WITH PRIMARY COMBINED IMMUNE DEFICIENCIES AND THEIR SURVIVAL IN CONDITIONS IN UKRAINE

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