Abstract
A 5-years multicenter prospective study on 201 patients with common variable immunodeficiencies and 101 patients with X-linked agammaglobulinemia over a cumulative follow-up period of 1,365 patient-years was conducted to identify prognostic markers and risk factors for associated clinical co-morbidities, the effects of long-term immunoglobulin treatment and the IgG trough level to be maintained over time required to minimise infection risk. Overall, 21% of the patients with common variable immunodeficiencies and 24% of patients with X-linked agammaglobulinemia remained infection free during the study. A reduction of pneumonia episodes has been observed after initiation of Ig replacement. During the observation time, pneumonia incidence remained low and constant over time. Patients with pneumonia did not have significant lower IgG trough levels than patients without pneumonia, with the exception of patients whose IgG trough levels were persistently <400 mg/dL. In X-linked agammaglobulinemia, the only co-morbidity risk factor identified for pneumonia by the final multivariable model was the presence of bronchiectasis. In common variable immunodeficiencies, our data allowed us to identify a clinical phenotype characterised by a high pneumonia risk: patients with low IgG and IgA levels at diagnosis; patients who had IgA level <7 mg/dL and who had bronchiectasis. The effect of therapy with immunoglobulins at replacement dosage for non-infectious co-morbidities (autoimmunity, lymphocytic hyperplasia and enteropathy) remains to be established. A unique general protective trough IgG level in antibody deficiency patients will remain undefined because of the major role played by the progression of lung disease in X-linked agammaglobulinemia and in a subset of patients with common variable immunodeficiencies.
Similar content being viewed by others
References
Orange JS, JS HEM, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006;117:S525–53.
Cunningham-Rundles C, Siegal FP, Smithwick EM, et al. Efficacy of intravenous immunoglobulin in primary humoral immunodeficiency disease. Ann Intern Med. 1984;101:435–9.
Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2002;109:1001–4.
Quartier P, Debre M, De Blic J, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr. 1999;134:589–96.
Roifman CM, Levison H, Gelfand EW. High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet. 1987;1:1075–7.
Chapel HM, Spickett GP, Ericson D, Engl W, Eibl MM, Bjorkander J. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol. 2000;20:94–100.
Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. 2001;135:165–74.
Roifman CM, Berger M, Notarangelo LD. Management of primary antibody deficiency with replacement therapy: summary of guidelines. Immunol Allergy Clin N Am. 2008;28:875–6.
Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol. 2010;125:1354–60.
Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis of clinical studies. Clin Immunol. 2010;137:21–30.
Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. 2008;122(1):210–2.
Plebani A, Soresina A, Rondelli R, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. 2002;104:221–30.
Chapel H, Lucas M, Lee M, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112:277–86.
Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93:190–7.
Mafee MF, Tran BH, Chapa AR. Imaging of rhinosinusitis and its complications: plain film, CT, and MRI. Clin Rev Allergy Immunol. 2006;30:165–86.
Bartlett JG, Dowell SF, Mandell LA, File Jr TM, Musher DM, Fine MJ. Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Dis. 2000;31(2):347–82.
Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.
Kainulainen L, Varpula M, Liippo K, Svedstrom E, Nikoskelainen J, Ruuskanen O. Pulmonary abnormalities in patients with primary hypogammaglobulinemia. J Allergy Clin Immunol. 1999;104:1031–6.
Quinti I, Soresina A, Spadaro G, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007;27:308–16.
Sweinberg SK, Wodell RA, Grodofsky MP, Greene JM, Conley ME. Retrospective analysis of the incidence of pulmonary disease in hypogammaglobulinemia. J Allergy Clin Immunol. 1991;88:96–104.
Wood P, Stanworth S, Burton J, et al. Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol. 2007;149:410–23.
Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous–lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004;114:415–21.
Ochs HD, Fischer SH, Wedgwood RJ, et al. Comparison of high-dose and low-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency diseases. Am J Med. 1984;76:78–82.
Carsetti R, Rosado MM, Donnanno S, et al. The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J Allergy Clin Immunol. 2005;115:412–7.
Alachkar H, Taubenheim N, Haeney MR, Durandy A, Arkwright PD. Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency. Clin Immunol. 2006;120:310–8.
Sanchez-Ramon S, Radigan L, Yu JE, Bard S, Cunningham-Rundles C. Memory B cells in common variable immunodeficiency: clinical associations and sex differences. Clin Immunol. 2008;128:314–21.
Park MA, Li JT, Hagan JB, Maddox DE, Abraham RS. Common variable immunodeficiency: a new look at an old disease. Lancet. 2008;372:489–502.
Wehr C, Kivioja T, Schmitt C, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111:77–85.
Acknowledgments
We wish to thank all the patients who participated to this study as well as their families, and the Jeffrey Modell Foundation. This work was supported by grant of the European Commission, HEALTH-F2-2008-201549
Conflict of Interests
The authors declare no competing financial interests.
Author information
Authors and Affiliations
Consortia
Corresponding author
Additional information
Italian Primary Immunodeficiencies Network (IPINet): Bari (D De Mattia, B Martire, F Cardinale, G Ranieri, F Silvestri), Bologna (M Masi), Bologna Centro Operativo AIEOP (A Pession), Cagliari (F Cossu), Catanzaro (E Anastasio), Catania (G Schillirò), Firenze (A Matucci, A Vultaggio, M Aricò), Milano (MC Pietrogrande, RM Delle Piane, C Panisi, G Cambiaghi), Napoli (C Pignata), Padova (MC Putti), Palermo (A Trizzino), Parma (P Bertolini), Pisa (R Consolini), Roma (AG Ugazio, M Duse, M Iacobini, V Moschese, C Cancrini, A Finocchi, AM Pesce, M Cagliuso, V Conti, G Granata, M Mitrevski), Salerno (F Cecere), Torino (PA Tovo, S Martino, D Montin), Varese (L Nespoli, M Marinoni, FP Pellegrini) and Verona (GA Cazzola).
Electronic supplementary material
Below is the link to the electronic supplementary material.
10875_2011_9511_MOESM1_ESM.doc
Supplemental Table I List of data collected in the Italian database: full blood counts, chemistries, serum immunoglobulin levels were performed four times per year. Chest and sinus CT scans were performed every 4 years, gastrointestinal endoscopy with biopsy every 2 years or when indicated. Disease-associated clinical co-morbidities such as X-ray defined pneumonia, acute and chronic sinusitis, meningitis, sepsis, diarrhoea, bronchiectasis confirmed by CT, histologically defined chronic lymphatic hyperplasia, chronic diarrhoea, splenomegaly confirmed by ultrasound, autoimmunity were collected in a structured questionnaire filed by one physician per centre on a yearly basis. (DOC 31 kb)
10875_2011_9511_MOESM2_ESM.doc
Supplemental Table II Age at diagnosis, age at the end of the study, basal IgG, IgA, IgM;, IgA, IgM and IgG trough levels at the end of the study and delta IgG, in 201 patients with CVIDs Results are expressed as milligrams per deciliter. (DOC 731 kb)
10875_2011_9511_MOESM3_ESM.doc
Supplemental Table III Age at diagnosis, age at the end of the study, basal IgG, IgA, IgM;, IgA, IgM and IgG trough levels at the end of the study and delta IgG, in 101 patients with XLA. Results are expressed as mg/dL. (DOC 219 kb)
Fig3
Supplemental Figure 1 Study design: 101 XLA patients and 201 CVIDs patients have been enrolled in a 5 years prospective study. Retrospective datasets were available from diagnosis. Mean age at diagnosis (±S.D.) and mean age at the last year of follow-up (FU) (±S.D.) are shown. (JPEG 32 kb)
Rights and permissions
About this article
Cite this article
Quinti, I., Soresina, A., Guerra, A. et al. Effectiveness of Immunoglobulin Replacement Therapy on Clinical Outcome in Patients with Primary Antibody Deficiencies: Results from a Multicenter Prospective Cohort Study. J Clin Immunol 31, 315–322 (2011). https://doi.org/10.1007/s10875-011-9511-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-011-9511-0