BLOOD CHEMISTRY- IMMUNOGLOBULINS. PLASMA PROTEINS.

1959 Marie J, Salet J, Debris P, Hebert S, Corbin JL, Bezri A. Edematous form of cystic fibrosis of pancreas with hypoproteinaemia and anaemia (French). Sem Hop Paris 1959; 35:2140-2146. [PubMed]
A report of the oedema and hypoproteinaemia in an infant with CF (also Lee PA et al, 1974; Gunn T et al, 1978 below). Also infants with CF presenting in this manner may have a false negative sweat test (MacClean WC, Tripp RW. J Pediatr 1973; 83:86-88). [PubMed]

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); 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)

1961 Shahidi NT, Diamond LK, Shwachman H. Anemia associated with protein deficiency. A study of 2 cases with cystic fibrosis. J Pediatr 1961; 59:533-42. [PubMed]
There was a fall in serum albumin from 4.0 to 2.6 g/dl over 30 days in an infant with CF fed a soy formula. The normal half life of 131I-labelled albumin excluded an exudative protein loosing enteropathy. The authors suggested that in CF infants soy protein absorption is more affected than cow’s milk protein.

Usually serum albumin is, rather surprisingly, within the normal range in CF unless there is significant liver involvement. However, it became apparent in a number of subsequent reports that soya based milk preparations were particularly likely to be associated with hypoproteinaemia in infants with cystic fibrosis (Fleisher et al, 1964 below; McClean &Tripp, 1974 below; Lee et al, 1974 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).

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] showed no decline in clinical wellbeing and better condition compared with this with high levels of IgG2.