IMMUNOGLOBULINS

1960 Green MN, Kulczycki LL, Shwachman H. Serum protein paper electrophoresis in patients with cystic fibrosis. Am J Dis Child 1960; 100:365-72. [PubMed]
Increased levels of gamma globulin, as determined by paper electrophoresis paralled the severity of the pulmonary disease. Subsequent studies confirmed the relationship of high immunoglobulin levels with severe chest involvement. The levels correlated with disease activity (Matthews WJ et al. N Eng J Med 1980; 302:245-249. below); also a subgroup of children with lower immunoglobulin levels appeared to have a better prognosis when followed over 5 years (Wheeler WB et al. J Pediatr 1984; 104:695-699 below). Also later more specific qualitative immunoglobulin abnormalities were reported as characteristic of the condition such as low IgG2 (Garside et al, 2005; Garside et al, 2007 both below)

1980 Matthews WJ Jr, Williams M, Oliphint B, Geha R, Colten HR. Hypogammaglobulinemia in patients with cystic fibrosis. N Eng J Med 1980; 302:245-249. [PubMed]
Serum immunoglobulins were measured in 419 people with cystic fibrosis. Twenty-two per cent of the 154 patients less than 10 years old had hypogammaglobulinemia-G, whereas the older patients had normal or elevated serum immunoglobulins. The patients with hypogammaglobulinemia had significantly less severe lung disease than did age-matched patients with normal or elevated IgG levels. The authors suggested that the progression of lung disease may be due in part to a hyper-immune response not present in those with the hypogammaglobulinaemia.

Subsequent studies of immunoglobulins (Garside JP et al. Pediatr Pulmonol 2004; 39:135-140) also showed a number with low immunoglobulins and more with low subgroups – particularly low IgG2. As in previous studies those few with high IgG levels were in worse clinical condition. A follow up of these patients (Garside et al. 2007; 42:125-130) showed there was a reduction in the prevalence of low levels of IgG2 from 29% to 10% over the 2-year period. Low levels of IgG2 were not associated with any decline in clinical well-being. Again the children with high levels of IgG2 had worse lung function, worse clinical and chest X-ray scores and higher levels of P. aeruginosa infection. Children with low IgG2 levels were not worse clinically compared to those with normal or high IgG2 levels. High IgG2 levels were associated with a worse clinical status

1984 Wheeler WB, Williams M, Matthews WJ Jr, Colten HR. Progression of cystic fibrosis lung disease as a function of serum immunoglobulin G levels: a 5-year longitudinal study. J Pediatr 1984; 104:695-699. [PubMed]
The children with persistent hypogammaglobulinemia G showed significantly better lung function, better weight for age, fewer hospitalizations for pulmonary exacerbations, less colonization with Pseudomonas aeruginosa, and slower decline in pulmonary functions than did age-matched patients with normal or high IgG levels. Death occurred in five of eight (63%) patients with hypergammaglobulinemia, three of 30 (10%) with normal levels and one of 32 (3%) with low levels. No deaths occurred in the 15 patients with persistent hypogammaglobulinemia.

These data indicate that children with cystic fibrosis and hypogammaglobulinemia G have milder lung disease and slower deterioration in pulmonary function than do age-matched patients with normal or elevated immunoglobulin G values. The mechanisms accounting for this finding are unclear (also Matthews et al, 1980 above; Garside et al, 2005; Garside et al, 2007 both below).

2004 Balfour-Lynn IM. Mohan U. Bush A. Rosenthal M. Intravenous immunoglobulin for cystic fibrosis lung disease: a case series of 16 children. Arch Dis Child 2004; 89:315-319. [PubMed]

Some children with severe cystic fibrosis (CF) lung disease develop chest tightness, recurrent dry cough, and intractable wheeze, often accompanied by deteriorating lung function and failure to expectorate sputum. In an attempt to reduce the use of regular oral corticosteroids, we treated a group of 16 such children with monthly courses of intravenous immunoglobulin (IVIG). The authors suggest that an n = 1 trial of IVIG in carefully selected patients with severe obstructive CF lung disease is worth considering, as for some it may lead to significant benefit.

2005 Garside JP, Kerrin DP, Brownlee KG, Gooi HC, Taylor JM, Conway SP. Immunoglobulin and IgG subclass levels in a regional pediatric cystic fibrosis clinic. Pediatr Pulmonol 2005; 39:135-40. [PubMed]
Total immunoglobulin levels were measured in 154 patients and IgG subclass levels were measured in 136 patients and compared to age-related normal population data and to levels reported in previously published studies of children with cystic fibrosis. Eleven patients had hypergammaglobulinemia (7.8% compared with 0-69% in the published literature). Patients with hypergammaglobulinemia had lower FEV1 percent-predicted values, and worse clinical and x-ray scores than controls. Three patients had hypogammaglobulinemia (1.9% compared with 0-10.8% in the published literature). There was no difference in any clinical parameter between controls and those with hypogammaglobulinemia. Nineteen patients (14%) had low levels of IgG1, and 40 patients (29%) had low levels of IgG2.

The low percentage of patients with abnormally high immunoglobulin levels compared with previous studies probably reflects the improved respiratory status of today's children with CF. The low percentage of those with low IgG probably reflects better nutritional status. The finding of worse lung function and clinical scores in patients with hypergammaglobulinemia agrees with the published literature. The high percentage of patients with low IgG2 was unexpected and had not been previously reported. The clinical significance of this in patients with CF is unknown. Also later follow-up of those with low Subclass 2 levels (Garside JP et al. Pediatr Pulmonol 2007; 42:125-130. [PubMed] below) showed no decline in clinical wellbeing and better condition compared with this with high levels of IgG2.

2007 Garside JP. Kerrin DP. Brownlee KG. Gooi HC. Taylor JM. Conway SP. Low gammaglobulin subclass 2 levels in paediatric cystic fibrosis patients followed over a 2-year period. Pediatr Pulmonol 2007; 42:125-130. [PubMed]
The aim of this study was to relate serum immunoglobulin G2 subclass levels in a large paediatric population with cystic fibrosis, to clinical status and antibody levels to Haemophilus influenzae type b and Streptococcus pneumoniae and to observe any changes over a 2-year period. IgG subclasses were measured in 131 patients. Results were compared with levels from age-related normal population data. The following clinical data were collected at baseline and 2 years later; genotype: height, weight, and BMI z-scores: FEV1 (as percent predicted): Shwachman-Kulczcyki and Northern chest X-ray scores: Pseudomonas aeruginosa status. Antibody levels to H. influenzae type b and S. pneumoniae measured at baseline were related to IgG2 level. There was a reduction in the prevalence of low levels of IgG2 from 29% to 10% over the 2-year period. Low levels of IgG2 were not associated with any decline in clinical well-being. Low levels of IgG2 alone were associated with low antibody levels to S. pneumoniae. Low levels of IgG2 and low levels of antibody to H. influenzae and S. pneumoniae were not associated with any decline in clinical well-being. Children with high levels of IgG2 had worse lung function, worse Shwachman-Kulczcyki and Northern chest X-ray scores and higher levels of P. aeruginosa infection. Children with low IgG2 levels were not worse clinically compared to those with normal or high IgG2 levels. High IgG2 levels were associated with a worse clinical status.