Journal of Clinical Immunology

, Volume 32, Issue 3, pp 454–466 | Cite as

Lessons Learned from Phagocytic Function Studies in a Large Cohort of Patients with Recurrent Infections

  • Baruch Wolach
  • Ronit Gavrieli
  • Dirk Roos
  • Sivan Berger-Achituv
Article

Abstract

Background

There is a paucity of data on the relationship between demographic characteristics, specific clinical manifestations, and neutrophil dysfunction, guiding physicians to decide which clinical signs and symptoms are a code for an underlying phagocytic disorder.

Methods

The data over a 21-year period of all adult and pediatric patients referred to our Laboratory for Leukocyte Functions with recurrent pyogenic infections were analyzed. Neutrophil function studies included chemotaxis, superoxide production (SOP), bactericidal activity (BA), and specific studies in case of suspected primary phagocytic disorder (PPD).

Results

Neutrophil dysfunction was found in 33.6% of 998 patients; chemotaxis in 16.6%, SOP in 6%, and BA in 24.5%. The younger the patient and the more organ systems involved, the greater the probability of finding phagocytic impairment. Impaired chemotaxis correlated with recurrent aphthous stomatitis, infections associated with elevated IgE, and purulent upper respiratory tract infections. Impaired SOP and BA correlated with deep-seated abscesses, recurrent lymphadenitis, sepsis, and bone and joint and central nervous system infections. PPDs were identified in 5.7%, chronic granulomatous disease in 4.8%, neutrophil glucose-6-phosphate dehydrogenase deficiency in 0.3%, leukocyte adhesion deficiency type 1 in 0.4%, and myeloperoxidase deficiency in 0.2%. Phagocytic evaluation contributed to the diagnosis of hyperimmunoglobulin-E syndrome (n = 21) and Chediak-Higashi syndrome (n = 3).

Conclusions

PPDs are identified in 5.7% of patients with recurrent pyogenic infections; in the remainder, phagocytic dysfunction may be related to deleterious effects of persistent infection, drug consumption, or disorders not yet established.

Keywords

Bactericidal activity Chediak–Higashi syndrome chemotaxis chronic granulomatous disease hyperimmunoglobulin-E syndrome leukocyte adhesion deficiency myeloperoxidase deficiency neutrophil phagocytic disorder recurrent pyogenic infections superoxide production 

Abbreviations

PID

Primary immunodeficiency disease

PPD

Primary phagocytic disorder

CGD

Chronic granulomatous disease

LAD

Leukocyte adhesion deficiency

HIES

Hyperimmunoglobulin-E syndrome

CHS

Chediak–Higashi syndrome

PMNs

Polymorphonuclear leukocytes

fMLP

N-formyl-methionyl-leucyl-phenylalanine

SOP

Superoxide production

BA

Bactericidal activity

H2O2

Hydrogen peroxide

DHR

Dihydrorhodamine

NADPH

Nicotinamide adenine dinucleotide phosphate

G6PD

Glucose-6-phosphate dehydrogenase

ROC

Receiver operating characteristic

LRTI

Lower respiratory tract infections

URTI

Upper respiratory tract infections

CNS

Central nervous system

BMT

Bone marrow transplantation

References

  1. 1.
    Geha RS, Notarangelo LD, Casanova JL, et al. International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee, primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol. 2007;120:776–94.PubMedCrossRefGoogle Scholar
  2. 2.
    Dinauer MC. Disorders of neutrophil function: an overview. Meth Mol Biol. 2007;412:489–504.CrossRefGoogle Scholar
  3. 3.
    Lakshman R, Finn A. Neutrophil disorders and their management. J Clin Pathol. 2001;54:7–19.PubMedCrossRefGoogle Scholar
  4. 4.
    Delamaire M, Maugendre D, Moreno M, et al. Impaired leucocyte functions in diabetic patients. Diabet Med. 1997;14:29–34.PubMedCrossRefGoogle Scholar
  5. 5.
    Alvarez I, Vazquez JJ, Fontan G, et al. Neutrophil chemotaxis and serum chemotactic activity in systemic lupus erythematosus. Scand J Rheumatol. 1978;7:69–74.PubMedCrossRefGoogle Scholar
  6. 6.
    Gemmell CG. Antibiotics and neutrophil function: potential immunomodulating activities. J Antimicrob Chemother. 1993;31(Suppl B):23–33.PubMedGoogle Scholar
  7. 7.
    Hasçelik G, Sener B, Hasçelik Z. Effect of some anti-inflammatory drugs on human neutrophil chemotaxis. J Int Med Res. 1994;22:100–6.PubMedGoogle Scholar
  8. 8.
    Wagner JG, Roth RA. Neutrophil migration during endotoxemia. J Leukoc Biol. 1999;66:10–24.PubMedGoogle Scholar
  9. 9.
    Wolach B. Exercise and the immune system - Focusing on the effect of exercise on neutrophil functions. In: Zaslav KR, editor. Sports Medicine and Sports Injuries. Croatia: InTech Open Access Publisher; 2012 (in press).Google Scholar
  10. 10.
    Wolach B, Baehner RL, Boxer LA. Review: clinical and laboratory approach to the management of neutrophil dysfunction. Isr J Med Sci. 1982;18:897–916.PubMedGoogle Scholar
  11. 11.
    van den Berg JM, Kuijpers TW. Educational paper: defects in number and function of neutrophilic granulocytes causing primary immunodeficiency. Eur J Pediatr. 2011;170:1369–76.Google Scholar
  12. 12.
    Roos D, de Boer M, Kuribayashi F, et al. Mutations in the X-linked and autosomal recessive forms of chronic granulomatous disease. Blood. 1996;87:1663–81.PubMedGoogle Scholar
  13. 13.
    Etzioni A. Leukocyte adhesion deficiencies: molecular basis, clinical findings, and therapeutic options. Adv Exp Med Biol. 2007;601:51–60.PubMedCrossRefGoogle Scholar
  14. 14.
    Ottonello L, Dapino P, Pastorino G, et al. Neutrophil dysfunction and increased susceptibility to infection. Eur J Clin Invest. 1995;25:687–92.PubMedCrossRefGoogle Scholar
  15. 15.
    Carulli G, Azzara A, Minnucci S, et al. Neutrophil dysfunction in patients with recurrent infections. Eur J Clin Invest. 1996;26:944–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Bondestam M, Håkansson L, Foucard T, et al. Defects in polymorphonuclear neutrophil function and susceptibility to infection in children. Scand J Clin Lab Invest. 1986;46:685–94.PubMedCrossRefGoogle Scholar
  17. 17.
    Brenneis H, Schmidt A, Blaas-Mautner P, et al. Chemotaxis of polymorphonuclear neutrophils (PMN) in patients suffering from recurrent infection. Eur J Clin Invest. 1993;23:693–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Boyum A. Isolation of mononuclear cells and granulocytes from human blood. Scand J Clin Lab Invest Suppl. 1968;97:77–89.PubMedGoogle Scholar
  19. 19.
    Falk W, Goodwin Jr RH, Leonard EL. A 48-well micro-chemotaxis assembly for rapid and accurate measurement of leukocyte migration. J Immunol Methods. 1980;33:239–47.PubMedGoogle Scholar
  20. 20.
    Weisbart RH, Golde DW, Gasson JC. Biosynthetic human GM-CSF modulates the number and affinity of neutrophil f-Met-Leu-Phe receptors. J Immunol. 1986;137:3584–7.PubMedGoogle Scholar
  21. 21.
    Wolach B, Gavrieli R, de Boer M, et al. Chronic granulomatous disease in Israel: clinical, functional and molecular studies of 38 patients. Clin Immunol. 2008;129:103–14.PubMedCrossRefGoogle Scholar
  22. 22.
    Clawson CC, Repine JE. Quantitation of maximal bactericidal capability in human neutrophils. J Lab Clin Med. 1976;88(2):316–27.PubMedGoogle Scholar
  23. 23.
    Vowells SJ, Sekhsaria S, Malech HL, et al. Flow cytometric analysis of the granulocyte respiratory burst: a comparison of fluorescent probes. J Immunol Methods. 1995;178:89–97.PubMedCrossRefGoogle Scholar
  24. 24.
    Verhoeven AJ, Bolscher BG, Meerhof LJ, et al. Characterization of two monoclonal antibodies against cytochrome b558 of human neutrophils. Blood. 1989;73:1686–94.PubMedGoogle Scholar
  25. 25.
    Petersen TK, Bysted BV, Jensen AL. Determination of the adhesive capability of canine polymorphonuclear neutrophil granulocytes using a fluorometric microtiter plate cellular adhesion assay. Vet Immunol Immunopathol. 1999;68:283–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Kuijpers TW, Tool AT, van der Schoot CE, et al. Membrane surface antigen expression on neutrophils: a reappraisal of the use of surface markers of neutrophil activation. Blood. 1991;78:1105–11.PubMedGoogle Scholar
  27. 27.
    Standardization of procedures for the study of glucose-6-phosphate dehydrogenase: report of a WHO scientific group. World Health Organ Tech Rep Ser. 1967;366:1–53.Google Scholar
  28. 28.
    Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections: an autosomal dominant multisystem disorder. N Engl J Med. 1999;340:692–702.PubMedCrossRefGoogle Scholar
  29. 29.
    Jeppson JD, Jaffe HS, Hill HR. Use of recombinant human interferon gamma to enhance neutrophil chemotactic responses in Job syndrome of hyperimmunoglobulinemia E and recurrent infections. J Pediatr. 1991;118:383–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Kaplan J, De Domenico I, Ward DM. Chediak–Higashi syndrome. Curr Opin Hematol. 2008;15:22–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Wolach B, Scharf Y, Gavrieli R, et al. Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB. Blood. 2005;105:61–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Wolach B, Ash S, Gavrieli R, et al. Acute lymphoblastic leukemia in a patient with chronic granulomatous disease and a novel mutation in CYBB: first report. Am J Hematol. 2005;80:50–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Wolach B, Eliakim A, Pomeranz A, et al. Cyclosporin treatment of hyperimmunoglobulin E syndrome. Lancet. 1996;347:67.PubMedCrossRefGoogle Scholar
  34. 34.
    Slatter MA, Gennery AR. Clinical immunology review series: an approach to the patient with recurrent infections in childhood. Clin Exp Immunol. 2008;152:389–96.PubMedCrossRefGoogle Scholar
  35. 35.
    Winkelstein JA, Marino MC, Johnston Jr RB, et al. Chronic granulomatous disease: report on a national registry of 368 patients. Medicine. 2000;79:155–69.PubMedCrossRefGoogle Scholar
  36. 36.
    van den Berg JM, van Koppen E, Ahlin A, et al. Chronic granulomatous disease: the European experience. PLoS One. 2009;4:e5234.PubMedCrossRefGoogle Scholar
  37. 37.
    Carr R. Neutrophil production and function in newborn infants. Br J Haematol. 2000;110:18–28.PubMedCrossRefGoogle Scholar
  38. 38.
    Wolach B, Sonnenschein D, Gavrieli R, et al. Neonatal neutrophil inflammatory responses: parallel studies of light scattering, cell polarization, chemotaxis, superoxide release, and bactericidal activity. Am J Hematol. 1998;58:8–15.PubMedCrossRefGoogle Scholar
  39. 39.
    Al-Nakeeb S, Thompson EN. Assessment of neutrophil chemotaxis and random migration in childhood: comparison between leading-front and lower surface count methods. Arch Dis Child. 1980;55:296–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Muniz-Junqueira MI, Peçanha LM, da Silva-Filho VL, et al. Novel microtechnique for assessment of postnatal maturation of the phagocytic function of neutrophils and monocytes. Clin Diagn Lab Immunol. 2003;10:1096–102.PubMedGoogle Scholar
  41. 41.
    Plebani A, Ugazio AG, Avanzini MA, et al. Serum IgG subclass concentrations in healthy subjects at different age: age normal percentile charts. Eur J Pediatr. 1989;149:164–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Israel Central Bureau of Statistics. Household expenditure survey 2007, Table 7.1: monthly income per household by type of locality. Available at: http://www.cbs.gov.il/publications09/1363/pdf/t07_1.pdf. Accessed 1 Sep 2011.
  43. 43.
    Newman PJ, Seligsohn U, Lyman S, et al. The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. Proc Natl Acad Sci U S A. 1991;88:3160–4.PubMedCrossRefGoogle Scholar
  44. 44.
    The Israeli National Genetic Database. Available at: http://www.goldenhelix.org/server/israeli/. Accessed 13 Nov 2011.
  45. 45.
    Behar DM, Yunusbayev B, Metspalu M, et al. The genome-wide structure of the Jewish people. Nature. 2010;466:238–42.PubMedCrossRefGoogle Scholar
  46. 46.
    Giraldo E, Hinchado MD, Garcia JJ, et al. Influence of gender and oral contraceptives intake on innate and inflammatory response: role of neuroendocrine factors. Mol Cell Biochem. 2008;313:147–53.PubMedCrossRefGoogle Scholar
  47. 47.
    Glasser L, Fiederlein RL. Functional differentiation of normal human neutrophils. Blood. 1987;69:937–44.PubMedGoogle Scholar
  48. 48.
    Golan H, Dalal I, Garty BZ, et al. The incidence of primary immunodeficiency syndromes in Israel. Isr Med Assoc J. 2002;4(11 Suppl):868–71.PubMedGoogle Scholar
  49. 49.
    Eades-Perner AM, Gathmann B, Knerr V, et al. ESID Registry Working Party: the European internet-based patient and research database for primary immunodeficiencies: results. 2004–06. Clin Exp Immunol. 2007;147:306–12.PubMedCrossRefGoogle Scholar
  50. 50.
    Hartl D, Lehmann N, Hoffmann F, et al. Dysregulation of innate immune receptors on neutrophils in chronic granulomatous disease. J Allergy Clin Immunol. 2008;121(375–382):e9.PubMedGoogle Scholar
  51. 51.
    Iancovici-Kidon M, Sthoeger D, Abrahamov A, et al. A new exon 9 glucose-6-phosphate dehydrogenase mutation (G6PD "Rehovot") in a Jewish Ethiopian family with variable phenotypes. Blood Cells Mol Dis. 2000;26:567–71.PubMedCrossRefGoogle Scholar
  52. 52.
    Wolach B, Ashkenazi M, Grossmann R, et al. Diurnal fluctuation of leukocyte G6PD activity: a possible explanation for the normal neutrophil bactericidal activity and the low incidence of pyogenic infections in patients with severe G6PD deficiency in Israel. Pediatr Res. 2004;55:807–13.PubMedCrossRefGoogle Scholar
  53. 53.
    Simon AJ, Lev A, Wolach B, et al. The effect of gentamicin-induced read through on a novel premature termination codon of CD18 leukocyte adhesion deficiency patients. PLoS One. 2010;5:e13659.Google Scholar
  54. 54.
    Minegishi Y, Saito M, Tsuchiya S, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448:1058–62.PubMedCrossRefGoogle Scholar
  55. 55.
    Mazzone A, Girola S, Fossati G, et al. Job syndrome (hyper-IgE) and hypo-IgA: a rare association of immunodeficiencies [article in Italian]. Recenti Prog Med. 1996;87:71–4.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Baruch Wolach
    • 1
    • 2
    • 3
  • Ronit Gavrieli
    • 1
  • Dirk Roos
    • 4
  • Sivan Berger-Achituv
    • 1
    • 2
  1. 1.Laboratory for Leukocyte FunctionsMeir Medical CenterKfar SabaIsrael
  2. 2.Department of PediatricsMeir Medical CenterKfar SabaIsrael
  3. 3.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  4. 4.Sanquin Research at CLB and Landsteiner Laboratory, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

Personalised recommendations