IgG1 SUBCLASS DEFICIENCY IN PATIENTS WITH CHRONIC FATIGUE SYNDROME

241 the 65-6% average reported for screened women aged 50 or more in five examinations of regular attenders in a Dutch screening to

project.3 Pathologists, in reporting, must stick to a histological categorisation but they should comment on the probability that changes found qualify as ANDI. The surgeon or radiologist who finds pathological terminology in conflict with his or her own appreciation of a breast abnormality should first examine whose is the greater aberration-of interpretation. Department of Pathology, University Medical School, Edinburgh EH8 9AG

migrate completely through the permeable filter. In this way the concentration-effect curve will be typically Gaussian, with nearly no chemotaxis at the very low concentrations and apparently no chemotaxis at the higher concentrations. Therefore only complete concentration-effect curves will give a. decisive answer about changes in the chemotactic sensitivity of cells. Department of Pulmonary Disease, State University Hospital Utrecht, 3511 GV

GERBEN K. TERPSTRA LEO A. M. J. HOUBEN

Utrecht, Netherlands

St Elisabeth Ziekenhuis, Amersfoort

HARM JAN HUIDEKOPER

T. J. ANDERSON 1. Ho

Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative disease. N Engl J Med 1985; 312: 146-51. 2 Hutter RVP and collaborators. Is fibrocystic disease of the breast precancerous? Arch Pathol Lab Med 1986; 110: 171-73. 3. Peeters PHM, Verbeeck ALM, Hendriks JHCL, Holland R, Mravunac M. The predictive value of positive results in screening for breast cancer by mammography m the Nijmegen programme. Br J Cancer 1987; 56: 667-71. 1

NEUTROPHIL ACCUMULATION IN CHRONIC OBSTRUCTIVE LUNG DISEASE

SIR-Neutrophil accumulation in inflamed tissue may have an important role in the pathology of emphysema and bronchiectasis. Dr Burnett and colleagues (Nov 7, p 1043) report peripheral polymorphonuclear leucocytes (PMN) with increased potential to digest extracellular connective tissue in both disorders. They also found enhanced chemotactic sensitivity to N-formyl-L-methionylL-leucyl-phenylalanine-methylester (FMLP-methylester) in PMN from emphysematous patients. In bronchiectasis, however, enhanced chemotactic sensitivity was not observed. Burnett and colleagues suggest that in bronchiectasis no increased chemotactic sensitivity was present or that endotoxin was implicated in the reduction of a possibly increased chemotactic sensitivity. However, these suggestions are a simplification which could lead to false conclusions. Increased chemotactic sensitivity could be expected due to concomitant infections in both emphysema and bronchiectasis. Burnett et al used FMLP-methylester as a chemotactic agent which is preferentially used in monocyte chemotaxis, while FMLP is used more suitably in PMN chemotaxis.1 Because different sensitivities to FMLP-methylester were found in both disorders, the investigation of other chemotactic stimuli would give a more definite answer about a chemotactic sensitivity of peripheral PMN. It can be assumed that chemotactic sensitivity of peripheral PMN is subject to many stimuli such as bacterial products, factors derived from tobacco smoke products, products derived from blood and alveolar cells, and any therapeutic agent. Thus the homogeneity of the group under study is important. In smoking controls Burnett et al found increases in chemotactic sensitivity to FMLP-methylester. We found no significant responses to FMLP, and other investigators,2,S using stimulated serum as attractant, found depressed activities. Hence it would be interesting to evaluate the results obtained by Burnett et al if their groups were subdivided by

PPK, Young AL, Southard GL. Methyl ester of N-formylmethionyl-leucylphenylalanine: Chemotactic responses of human blood monocytes and inhibition of gold compounds. Arthritis Rheum 1978, 21: 133-36. 2. Terpstra GK, Houben LAMJ, Huidekoper HJ. Pharmacological modulation of neutrophil chemotaxis into the airway lumen: Its consequences in inhalation therapy. In: Peeters H, ed. Protides of the biological fluids Cambridge: Pergamon Press, 1987, 35: 255-58. 3 Corberand J, Laharrague P, Nguyen F, et al Effect of tobacco smoking on the functions of polymorphonuclear leukocytes. Infect Immun 1979; 23: 577-81. 4. Totti N III, McCusken KT, Campbell EJ, Griffin GL, Senior RM. Nicotine is chemotactic for neutrophils and enhances neutrophil responsiveness to chemotactic peptides Science 1984; 223: 169-71. 5. Dahinden CA, Clancy RM, Hugl TE. Stereospecificity of leukotriene B4 and structure function relationships for chemotaxis of human neutrophils. J Immunol 1984; 133: 1477-82. 6. Maderazo EG, Woronick CL. A modified micropore filter assay of human granulocyte leukotaxis. In: Gallin JI, Quie PG, eds. Leukocyte chemotaxis: Methods, physiology and clinical implications. New York. Raven Press, 1978; 43-45

IgG1 SUBCLASS DEFICIENCY IN PATIENTS WITH CHRONIC FATIGUE SYNDROME

SiR,—There have been several reports of altered immune function in patients with chronic fatigue syndrome. In a few patients this syndrome follows acute infectious mononucleosis and altered immune responses to Epstein-Barr virus (EBV) have been found in this group and in those with no history of Paul-Bunnellpositive glandular fever. Patients within this group are said to have chronic mononucleosis (CMS) but in fact they may have a subtle immune disorder rather than active EBV infection.’1 Gammaglobulin isotype deficiency has been described in CMS and immunoglobulin therapy can improve symptoms in this group of patients.2 We report two patients with an unexplained chronic fatigue syndrome. Neither patient had aberrant EBV immune responses but both had a specific deficiency of IgGI subclass. The first case was a 32-year-old female care-assistant with an 18-month history of fatigue, depression, intermittent sore throat, malaise, myalgia, arthralgia, and lymphadenopathy. This syndrome preceded by an acute Paul-Bunnell-negative glandular-feverExamination was normal. White cell count (WBC) was 9800/1 (lymphocytes 4000/1), erythrocyte sedimentation rate (ESR) 3 mm/h, and antibody to human herpesvirus 6 (anti-HHV6) was strongly positive but antibodies to EBV viral capsid antigen 32 (VCA 32) and early antigen (EA) were negative. The second case was a 24-year-old male electrical engineer with a 16-month history of fatigue, myalgia, and intermittent sore throat. This syndrome was preceded by an acute Paul-Bunnell-negative glandular-fever-like illness. Examination was normal. WBC was 7600/ul (lymphocytes 2200/)il) and ESR 1 mm/h. The patient was negative for anti-HHV6 anti-VCA 32, and anti-EA. Both patients were repeatedly Paul-Bunnell negative over a follow-up of 4 months. Antibody titres to Toxoplasma, cytomegalovirus (CMV), and Mycoplasma were low. There was no evidence on co-culture of lymphocytes with human cord-blood mononuclear cells of cytopathic effect or reverse transcriptase activity of HIV-1 infection. Immunoglobulin concentrations and lymphocyte phenotype analyses are shown in the table. Both patients had IgGI1 concentrations below normal at the first visit, which contributed to the low total IgG values. All other immunoglobulin isotypes and IgG subclass concentrations were normal. 4 months later these had was

like illness.

smoking status. Burnett and colleagues used blind well assays with FMLP-ester as chemotactic agent. In such assays many cells migrate but only a small number migrate completely through the entire thickness of the permeable filter. Therefore counts of these cells only provide information about the fastest portion of the whole population. Information about the chemotactic sensitivity of the whole population is more properly obtained by chemotactic indices, which combine information about distances migrated and corresponding numbers of cells.6 Monitoring chemotactic sensitivity at a fixed concentration of FMLP does not imply smaller effects at lower concentrations. When constructing a concentration-effect curve gradients will be established in the filter system and, when counting the cells at the bottom of the upper (permeable) filter, the largest number of cells will be found at an optimum concentration at the bottom of the cell-permeable filter. At higher concentrations cells will find an optimum concentration of FMLP inside the permeable

patients had low T4/T8 ratios at the first visit which had returned to

filter and

normal 4 months later.

not at

the bottom of this filter; thus the cells will

not

returned

to

normal in

case

1 but

remained low in

case

2. Both

242 IMMUNOGLOBULIN CONCENTRATIONS AND LYMPHOCYTE PHENOTYPES IN TWO PATIENTS WITH CHRONIC FATIGUE SYNDROME

*Normal ranges (from Edwards AJ, e2 al.

ClinExpImmunoII984; 58:420-27): IgG =7 2-16-2 g/l,IgGI= =3 3 2-10 g/1, T4 = mean 456 (SD 157/t),T8 =272 (124/1), and B 86 (42/)it).

The finding of IgGl deficiency in these patients is novel, as lone deficiency of this subclass is rare and affected patients appear to have common variable hypogammaglobulinaemia. In a large study of IgG subclass deficiencies, Soderstrom et aP found only 16% of these patients had pure IgGI deficiency and of these, 9% had depressed T4/T8 ratios, although 54% had abnormal response to the mitogenic lectins phytohaemagglutinin and concanavalin A. Most patients were examined because of recurrent bacterial a infections. The origin of the defect described here may be either. failure of T-cell help or excess subclass-specific suppression. The transitory nature of the defect in case 1 argues against permanent deletion of IgGl-secreting B-cells. If an infectious agent is responsible for the symptoms and objective abnormalities described in these case reports, then what is it? EBV, CMV, and HIV are unlikely candidates. Krueger et al4 described a patient with fatigue and high titres of antibody to HHV6, though the prevalence of this antibody within the normal community has yet to be established. Only one of our cases had strongly positive indirect immunofluorescence to HHV6 antigen and we failed to recover the virus from either patient. Further scrutiny of cases with chronic fatigue may reveal a range of subtle immunological abnormalities, of which altered expression of latent EBV infection is only one. As yet there is no clue to whether a single agent or a single host defect can account for cases such as these. We thank Dr Crawford (Royal Postgraduate Medical School) for EBV serology, Dr R. Tedder (Middlesex Hospital Medical School) for HHV6 serology, Prof A. Milford Ward (Royal Hallamshire Hospital, Sheffield) for assaying immunoglobulin subclasses, and Ruth Beattie for reverse transcriptase assays. Sections of Communicable Diseases and Immunological Medicine, Northwick Park Hospital and Clinical Research Centre, Harrow HA1 3UJ

1.

ROBERT READ GAVIN SPICKETT JENNIFER HARVEY ANDREW J. EDWARDS H. ELLIOTT LARSON

Jones JF, Straus SE. Chronic Epstein-Barr virus infection. Annu Rev Med 1987; 38: 195-209

2. DuBois RE. Gammaglobulin therapy for chronic mononucleosis syndrome. AIDS Res 1986; 2: S191-95. 3. Soderstrom T, Soderstrom R, Avanzini A, et al. Immunoglobulin G subclass deficiencies. Int Archs Allergy Appl Immunol 1987; 82: 476-80. 4. Krueger GRF, Koch B, Ablashi DV Persistent fatigue and depression in patient with antibody to human B-lymphotropic virus. Lancet 1987; ii: 36

BENZODIAZEPINES IN ANXIETY

SiR,—Your correspondents’ remarks (Nov 7, p 1080; Dec 12, p 1406) on benzodiazepines may reflect personal opinion, but statements such as "there is no use for these drugs in the treatment of anxiety" are not justified. Several well-controlled trials prove that benzodiazepines have a place in the treatment of various types of anxiety disorders.We can all see the possible hazards of prescribing these drugs but personal opinions should not be elevated to the status of generalisations without scientific back-up. Dr Carney and his colleagues contradict themselves, finding "no place for benzodiazepines in the treatment of anxiety" yet one sentence later conceding that "they may be used in states of acute psychiatric disturbance". An acute anxiety state is an acute psychiatric disturbance, as any doctor working in an emergency service would know. As for Professor Cohen’s questions about the sort of patients who should receive benzodiazepines I, strongly reinforcing Dr

comment (Nov 28, p 1273), would refer him to three psychopharmacology textbooks edited by’American, Austrian, British, and German authors (to reflect the international homogeneity of views on this topic) that clearly state the indications for benzodiazepines.1-3 A treatment of proven efficacy should not be withheld from patients with acute or chronic anxiety states. One person’s opinion should not result in the removal of benzodiazepines when scientific evidence points in the opposite direction. It is the doctor’s responsibility to weigh carefully the benefits and risks when considering whether to prescribe a benzodiazepine for a patient.

Sandler’s standard

Department of Psychiatry Research, Hillside Hospital, Long Island Jewish Medical Center, Glen Oaks, New York 11004, USA 1.

W. WOLFGANG FLEISCHHACKER

Rickels K, Schweizer EE. Current pharmacotherapy of anxiety and panic. In: Meltzer H, ed. Psychopharmacology: the third generation of progress. New York: Raven Press, 1987: 1193-205.

Poldinger W, Wider I. Psychopharmakotherapie bei Angstsyndromen, phobischen Syndromen und Zwangssyndromen. In: Langer G, Heimann H, eds Psychopharmaka. Vienna: Springer, 1983. 447-67. 3. Rickels K, Downing W, Winokur A. Antianxiety drugs: Clinical use m psychiatry. In. Iversen LL, Iversen SD, Snyder SH, eds. Handbook of psychopharmacology XIII: Biology of mood and antianxiety drugs. New York. Plenum, 1978: 395-430

2.

VITAMIN

B12 AND SEAWEED

SiR,—We need to know if non-animal foods such as seaweed, algae, and fermented soya products can contribute to human vitamin B12 needsl,2 because vegetarian and macrobiotic life styles are gaining popularity. Little is known about the vitamin B12 content of (and bioavailability from) these food products.3,4 As part of a study on macrobiotically fed Dutch children we analysed about forty plant foods for vitamin B12 by an in-house radioassay based on the method of Lau et aP with pure intrinsic factor (Sigma) as binder and cyanocobalamin as standard. The between-assay coefficient of variation was 5-8% based on a twentyfold analysis of pooled milk samples (8-5 ± 0-5 )J.g per 100 g). Samples were extracted by autoclaving (120°C) for 10 min in 0-1 mol/1 sodium acetate buffer pH 4-6, containing freshly added 0 005% potassium cyanide. Products rich in vitamin B’2 were also measured by microbiological assay (Difco). Neither in fermented soya products (tempeh, shoyu, tamari, rice miso, barley miso, tofu) nor in other fermented products (amesake rice, umeboshi prunes) did we find measurable vitamin B12 (all below 0-02 I1g per 100 g). Small amounts (0-02-0-5 I1g per 100 g) were found in barley malt syrup, sourdough bread, parsley, and shitake. Some algae were rich in vitamin B12 (table). For some products conflicting results between the two assays were obtained, as reported by Herbert et al. The higher value for spirulina with the Lactobacillus leichmanni assay may be due to corrinoid-like EI2 analogues giving a growth response in the microbiological assay but with no affinity for binding to intrinsic factor. The lower microbiological assay levels found for kombu, wakame, and kelp are more difficult to explain but indicate that intrinsic factor may have some affinity for corrinoids that are non-responsive to L leichmanni. Interesting is the high vitamin B12 content of nori, with good agreement between the two assays. This high level was confirmed in other samples of this product from different sources in the USA and Japan (table). Is the vitamin B12 in nori available to the human body? Preliminary findings in vitamin-B12-deficient macrobiotically fed