THE SWEAT TEST

Undoubtedly the major advance during the Fifties was the recognition of the increased salt content of the sweat in people with CF by Paul di Sant’Agnese in 1953 (below). This followed the report of Kessler and Andersen in 1951 (below) of heat prostration in children with CF that occurred during a New York heat wave in August 1948. Subsequently the availability of the sweat test permitted an accurate diagnosis when CF was suspected and gradually replaced the more invasive duodenal intubation. Diagnosis by sweat analysis became more practicable, accurate, safe and more generally available when localised sweating was stimulated by the pilocarpine iontophoresis, as described by Gibson & Cooke, in 1959, (below) rather than by the various potentially dangerous methods of heating the whole patient to stimulate sweating. The availability of the sweat test permitted the recognition of people with CF who had adequate pancreatic function – so-called “pancreatic sufficient” individuals. Finally, it became apparent that if the test was carried out by inexperienced staff erroneous results were not infrequent; eventually much attention was paid to ensuring that adequate standards were in place.

1951 Kessler WR, Andersen DH. Heat prostration in fibrocystic disease of the pancreas and other condition. Pediatrics 1951; 8:648. [PubMed]
One of the most important papers up to that time from New York. Walter Kessler, the senior resident at the time, and Dorothy Andersen reported 12 children with heat prostration. Ten were admitted during a New York heat wave in 1948 and no less than seven were known to have cystic fibrosis. These were the days before air conditioning was generally available in New York and 1948 was a particularly hot summer. Paul di Sant’Agnese was working with Dorothy Andersen at the time and looking after her patients, and later said that he treated these particular infants as Andersen was away vacationing in Europe when they were admitted! The authors of this present report queried whether the sweat glands, as well as the glands of the pancreas and other organs, were inadequate in function or alternatively whether a low grade infection lowered the margin of tolerance to increased temperatures.
At the time of this report there was no explanation as to why infants with CF were particularly susceptible to heat prostration and salt depletion – fortunately Paul di Sant’Agnese decided to find out! This was the first report that children with CF were particularly susceptible to heat. It was this original incident that eventually led Paul di Sant’Agnese to search for the reason for salt depletion in many of these CF infants and eventually to his recognising the abnormally high sweat sodium and chloride, and to a lesser extent potassium. This was undoubtedly the first and most important major advance in the understanding of the causation of CF up to that time (see di Sant’Agnese et al, 1953 below).

1953 Darling RC, di Sant’Agnese PA, Perera GA, Andersen DH. Electrolyte abnormalities of the sweat in fibrocystic disease of pancreas. Am J M Sc 1953; 225:67-70. [PubMed]
The first report of elevated sweat electrolytes in cystic fibrosis. di Sant’Agnese collaborated with Bob Darling (figure 8) who was the head of the Rehabilitation Department of the Columbia Presbyterian Hospital. In this department there was a constant temperature room and a method of collecting sweat. Initially two teenagers with CF and two controls were selected and although the sweating rate was similar the level of electrolytes was much higher in the patients with cystic fibrosis. Subsequently sweat from nine CF children and eight controls showed chloride more than three times higher in the people with CF than in the controls. This was an unexpected finding quite unrelated to any previously recognised abnormalities in the condition (di Sant’Agnese et al, 1953 below) but it was the most important observation since the clear identification of CF as a specific entity by Dorothy Andersen in 1938.

1953 di Sant’Agnese PA, Darling RC, Perera GA, Shea E. Sweat electrolyte disturbances associated with childhood pancreatic disease. Am J Med 1953; 15:777-784. [PubMed]
In this study there were 50 patients with CF, 9 with other pancreatic diseases and 50 controls. All the CF patients had similar elevations in the sweat electrolytes. Their adrenal and renal function was normal. The authors considered the findings to justify abandoning the term “mucoviscidosis” and returning to the unsatisfactory term “cystic fibrosis of the pancreas” until a better one was proposed.

1953 di Sant’ Agnese PA, Darling RC, Perera GA, Shea E. Abnormal electrolyte composition of the sweat in cystic fibrosis: Clinical significance and relationship to the disease. Pediatrics 1953; 12: 549-563. [PubMed]
This is the main paper that di Sant’Agnese himself quotes as describing the sweat electrolyte abnormality expanding on the paper of Darling et al, 1953 (above). Di Sant’Agnese mentions the original report of Kessler and Andersen 1951 (above) and also that the susceptibility of patients with CF to heat in the summers was noted also during subsequent summers after 1948. Paul Quinton more recently recalls that di Sant’Agnese told him that the development of heat tolerance among troops sent to North Africa was attributed to adaptations to sweating, so di Sant’Agnese pursued excessive salt loss in the sweat as the most likely origin of volume depletion during the high heat stress (Quinton, 1999 below). Bob Darling was head of Rehabilitation at Columbia Presbyterian Hospital and had a constant temperature room. Di Sant’Agnese decided “as a shot in the dark to see if sweating function was impaired in CF patients that would lead to a smaller than normal volume of sweat, or whether there was something wrong with the sweat electrolyte concentration”. di Sant’Agnese continued - “In April 1952 two teenage children with CF and two controls were put in the constant temperature room and their sweat then analysed for electrolytes. To my surprise and excitement the answer was right there. There was a tremendous difference in the sweat electrolyte concentration between the two groups”. “In contrast the sweating rate was similar in the two groups”. (Described in detail by Paul di Sant’Agnese. Experiences of a Pioneer Researcher. In: Doershuk CF (ed.) Cystic Fibrosis in the 20th Century 2001; Fanos JH. 2008; 17-35.). Sant’Agnese and colleagues showed the sweat abnormality was unrelated to renal or adrenal disease and was definitely related to sweat losses.

For this present paper they examined 43 people with CF, nine patients with other pancreatic diseases and 50 controls in a room at 32.2 C for one to two hours. Sweat was collected onto dry gauze under adhesive waterproof plaster. Sweat chloride in the CF patients was 106 (60-160) meq/l, in controls and other pancreatic diseases only 32 meq/l (4-80) and in CF the Na 133 (80-190), and in controls 59 (10-120).

This was undoubtedly the most important advance in the understanding of CF up to that time. However, astonishingly, di Sant’Agnese recalls the paper received a very cool reception at the 1953 meeting of the American Pediatric Society with not a single question! Also when presented before Jas Kuno, apparently a distinguished sweat physiologist, Kuno uttered one word -“impossible”- and walked out of the room! It is also said that even di Sant' Agnes's close colleague Dorothy Andersen was at first reluctant to accept the findings. However, and perhaps predictably, Harry Shwachman soon visited di Sant’Agnese in New York; he was impressed and with his usual alacrity and energy was able to present a large supportive series by October 1954 much to di Sant’Agnese’s delight!

1956 Webb BW, Flute PT, Smith MJH. The electrolyte content of the sweat in fibrocystic disease of the pancreas. Arch Dis Child 1957; 32:82-84. [PubMed]
An early UK study from the Departments of Chemical Pathology and Paediatrics, Kings College Hospital, London - the first UK study since di Sant' Agnese's description of the sweat abnormality (di Sant' Agnese et al, 1953 above).. Twelve patients with CF, aged between 11 months and six years, and 20 controls had sweat electrolytes estimated which confirmed the findings of di Sant’Agnese et al, 1953. Controls had sweat sodium of 27 (4-32) meq/l and chloride of 23 (9-40) meq/l and the CF children sodium values of 125 (72-157) and chloride values of 127 (68-148) meq/l.
The patient was “placed in a plastic bag tied loosely around the neck (figure 13) and allowed to lie in a cot or bed covered with three or four blankets.The sweat was collected on weighed filter papers which were applied to the back (figure 14). “In some instances the children were restive at first but quickly became used to the conditions”.

Figure 13: Collection of sweat in a plastic bag tied loosely around the neck	Figure 14: Gauze applied to the back to collect the sweat.
Figures from paper with permission of BMJ Publishing Group

Subsequently there were a number of complications with this method of sweat testing in some hospitals, as a result of over-heating small debilitated CF infants in this manner, including one fatality (Misch & Holden, 1958 below).

1956 Shwachman H, Gahm N. Studies in cystic fibrosis. Simple test for detection of excessive chloride on the skin. N Eng J Med 1956; 255:999-1001. [PubMed]
Due to the high level of chloride in the sweat, people with CF produce white fingerprints on plates impregnated with silver nitrate and potassium chromate. Dr Kulczycki (long time colleague of Harry Shwachman’s) performed 1443 control tests at an institution for the mentally handicapped.

The authors suggested “the plate test” as a screening test for CF but it never became popular. When the sweat test became more readily available in the early Sixties following the publication of Gibson and Cooke (1959 below), the result was so important that it was preferred to the semi-quantitative plate test.

Subsequently Kulczycki (Am J Dis Child 1960; 100:174-180) screened 3036 school children with the plate test. There were 2% false positives on first test and no children with CF were identified. Authors suggested it would be better to use the test in well-baby clinics.
Although the total heating of the child to induce sweating was obviously causing serious problems at times, the Gibson & Cooke iontophoresis method was soon to be reported in 1959. Subsequent screening tests using chloride electrodes, paper strips, salivary electrolytes, meconium albumin and faecal trypsin have all been relative failures with the exception of blood immunoreactive trypsin in neonates which has become internationally accepted as the basis of neonatal screening programmes (Crossley et al, 1979 above).

1956 Johnston W H. Salivary electrolytes in fibrocystic disease of the pancreas. Arch Dis Child 1956; 31: 477-480. [PubMed]
A study from Great Ormond Street Hospital in London showing elevated sodium and chloride in the stimulated saliva of 31 patients with CF compared with 63 controls. The separation was not such that the test had diagnostic value and also the values depended on the rate of flow.
Prader & Gautier (Helv Paediat Acta 1955; 10:56) had found the saliva sodium was increased in cystic fibrosis. Unfortunately these various studies the electrolyte content CF saliva did not prove helpful in either the diagnosis or the understanding of the nature of the CF basic defect (also Lawson et al. 1956. below). The studies were an natural follow-on from the recently described sweat electrolyte abnormalites - estimation of the elctrolyte content of the finger nails was still to come (Kopito et al, 1965 below)!

1957 MacFarlane JCW, Norman AP, Stroud CE. Fingerprint sweat test in fibrocystic disease of the pancreas. BMJ 1957; (5039):274-275. [PubMed]
The finger print test, devised by Shwachman & Gahm, 1956, (above) was tried in view of the difficulties, and even dangers, of collecting sweat by heating the whole patient, in the years before the Gibson and Cooke iontophoresis method was described in 1959. In fact, children were known to have died due to overheating in an attempt to obtain sweat (Misch & Holden, 1958 below). The 54 children with CF in this study were all strongly positive with the finger print test. The authors suggested the test was useful and safe – but they considered it needed further evaluation. However, within 2 years the pilocarpine iontophoresis method of sweat stimulation of Gibson and Cooke (1959 below) would be described and this would become the standard method of sweat stimulation at the Hospital for Sick Children, London – although considerably more time-consuming and also open to serious errors if performed by an inexperienced operator as was later documented (Smalley et al, 1978 below). Subsequently a study confirming the value of the Gibson and Cooke test was performed at the Great Ormond Street Hospital by Tom McKendrick, a Senior Registrar there at the time (McKendrick, 1962 below).

1958 Misch KA, Holden HM. Sweat test for diagnosis of fibrocystic disease of the pancreas. Arch Dis Child 1958; 33:179-180. [PubMed]
Fatal collapse of a patient having “Shwachman sweat test” (see figure above in Webb et al, 1956) which involved the whole body being enclosed in a plastic bag as a method of heating the patient to obtain an adequate sample of sweat. This boy aged 13 months was heated for 3 hours and developed hyperpyrexia, vomited copiously, became comatose and he died after 14 hours.
Shwachman commented that in his unit 1900 tests had been perfomed by the bag method with only one serious untoward reaction of hyperpyrexia and convulsions – the patient recovered and did not have cystic fibrosis. In the UK there were a number of serious reactions which never appeared in journals, before the Gibson & Cooke pilocarpine method of inducing sweating was described in 1959.

1959 Gibson LE, Cooke RE. A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilising pilocarpine electrophoresis. Pediatrics 1959; 23:545-549. [PubMed]
This classic paper described the pilocarpine iontophoresis method for stimulating sweating to obtain sweat for analysis. It was a major advance, as prior to this these frail infants were often heated in blankets or plastic bags. The pilocarpine iontophoresis method is still used by most laboratories for stimulating localised sweating (figure 22).

Subsequently, as more laboratories performed the test caution was expressed as when performed by inexperienced operators mistakes occurred. These mistakes often resulted in CF being over diagnosed when the sweat result was falsely high which could happen if the sweat specimen was allowed to evaporate. Also, there were reports of burns under the electrodes. The first report of such major diagnostic errors in the UK was from Birmingham (Smalley et al, Lancet 1978; ii: 415-417 below) from Prof. Charlotte Anderson’s unit but soon others followed (David TJ & Phillips BM. Lancet 1982; ii: 1204-1205).

In Leeds we found that 7 (4%) of the first 179 children referred for Comprehensive Assessment of their CF from various parts of the UK did not have the condition (Shaw NJ & Littlewood JM. Arch Dis Child 1987; 62:1271-1273). The consequences of a false diagnosis of CF frequently had disastrous socio-medical consequences e.g. one mother had been sterilised to avoid another child with CF as it was mistakenly thought her first child had CF. Many parents had avoided having further children; some parents took legal action against the paediatrician involved in the mistaken diagnosis.
So the sweat test is an excellent test if carried out correctly by experienced laboratory staff but can be disastrous if performed by inexperienced staff as an occasional procedure and the result accepted uncritically by the paediatrician and considered with all the other clinical and laboratory evidence when making a diagnosis of cystic fibrosis.

1960 Anderson CM, Freeman M. Sweat test results in normal persons of different ages compared with families with fibrocystic disease of the pancreas. Arch Dis Child 1960; 35: 581-587. [PubMed]
Charlotte Anderson (from Melbourne and later Birmingham UK) showed no abnormality in the sweat electrolytes from parents or siblings of people with CF nor in patients with other chronic chest diseases. A wide scatter of results was obtained in adults for example 34/100 normal adults had sweat sodium levels over 60meq/l. Anderson states that “determination of sweat sodium and chloride loses much of its value” in adults. Also intradermal mecholyl chloride was used to stimulate sweating in Anderson’s study.
This method of stimulating sweating did not become popular and we heard of one serious reaction with the method. The details of the methods used in the study were criticised by di Sant’Agnese as a different dose of mecholyl was used in the different age groups and this may have affected the rate of sweating which would influence the concentration of electrolytes (also Simmonds EJ, et al. Arch Dis Child 1989; 64:1717-1720. [PubMed] ). He considered that the conclusions drawn by Anderson and Freeman “were not warranted by their limited experience”. Fortunately during the Sixties the sweat test by the Gibson and Cooke pilocarpine iontophoresis method, first described in 1959 (above), slowly became the gold standard. Later studies from Great Ormond Street, London (McKendrick et al, 1963 below) showed the sweat electrolytes were insignificantly higher than normal in obligatory heterozygotes.

1961 Shwachman H, Antonowicz I, Stern M. The sweat tests in cystic fibrosis. Am J Dis Child 1961; 102:769.
An interesting report where Shwachman describes performance of over 2000 “bag” sweat tests – 335 in patients with CF. The mean chloride level in CF was 113 meq/L and mean sodium 112meq/L compared with controls’ values of 23 and 23 respectively. The bag method was abandoned in 1958 in preference to the pilocarpine method of Gibson and Cooke (1959 above) with which the bag results were compared.

1961 Elian E, Shwachman H, Hendren WH. Intestinal obstruction in the newborn infant; usefulness of the sweat electrolyte testing differential diagnosis. N Eng J Med 1961; 264:13-16. [PubMed]
The authors managed to perform pilocarpine iontophoresis sweat tests in the first four days of life in 37 babies- a difficult feat at this early age. Another six newborns with intestinal obstruction were tested – the four with CF were all sweat test positive and the two with negative sweat tests had respectively Hirschprung’s disease and ileal atresia.
So sweat tests were already positive in the newborn period in infants with CF but an experienced and skilful technician would be required to perform the investigation. If an urgent answer is required at the present time a check on the infant for the presence of CF mutations would be helpful in most instances.

1962 McKendrick T. Sweat sodium levels in normal subjects, in fibrocystic patients and their relatives and in chronic bronchitis patients. Lancet 1962; I: 183-186.
A study by Dr Tom McKendrick, a senior registrar working at Great Ormond Street, London with Dr (now Dame) Barbara Clayton, the chemical pathologist, and Dr Archie Norman, using the recently described Gibson and Cooke pilocarpine iontophoresis method of sweat stimulation (Gibson & Cooke, 1959 above). In normal children sweat sodium was almost always less than 60 meq/l rising from 22 to 44 in the first 14 years and rising to 55 in adults. 95% of people with CF had sodium levels over 70 and parents and siblings showed levels slightly greater than normals. The levels were normal in chronic bronchitis patients i.e. there were no people with CF amongst those considered to have chronic bronchitis.
The conclusion was that the “The wide variation of results both in single subjects and within groups of similar subjects limit the value of the test. It is useful only for confirming the diagnosis of cystic fibrosis” – for which, of course, it proved of immense value and to be a major advance, eventually becoming the “gold standard” method of sweat testing.

1962 Shwachman H. The sweat test. Pediatrics 1962; 30:167-171. [PubMed]
A commentary on the relatively recently described sweat test by Harry Shwachman and the article is full of wise advice. While the sweat test is specific for CF the following factors were crucially important in diagnosis. Maintaining a high degree of suspicion noting the great variability of the disease; the presence of elevated electrolytes alone does not establish the diagnosis; many factors influence the result – not least the experience of the laboratory; diagnosis should not be made lightly but only after careful appraisal of the patient, the family history and laboratory evidence. Heterozygotes cannot be detected with the sweat test.
One suspects that over diagnosis was a relatively common problem in Shwachman’s experience due false high values of sweat electrolytes – this article discusses some of the confounding and other factors that affect the test. A key publication from Charlotte Anderson’s unit in the UK documented the frequent overdiagnosis of the condition in the UK (Smalley et al, 1978 below) and was of great importance in alerting UK paediatricians to the problem.

1963 Lobeck CC, McSherry NR. Response of sweat electrolyte concentrations to 9 alpha-fluorohydrocortisone in patients with cystic fibrosis and their families. J Pediatr 1963; 62: 393-398. [PubMed]
Patients with CF failed to show a significant decrease in their sweat electrolytes after administration of oral 9-alpha fluorohydrocortisone (3.0 mg per square meter for two days). Parents, siblings of people with CF and controls all had a significant decrease in the concentration of their sweat electrolytes after this challenge – for example the fall in chloride in parents was - 40.8%, in controls - 43.6%, in siblings -35.6%, but people with CF only had -1.1% reduction in their sweat chloride level.

This was a practically useful paper when there was a problem with diagnosis and there was a marginal sweat test result -– particularly pre-1989 before genetic mutations could be determined. We used the test on a number of occasions and found it to be helpful when the diagnosis was in doubt and the sweat test result borderline with chloride values of around 50 – 70 meq/l. Margaret Hodson also found the fludrocortisone suppression test useful in adults with marginal sweat test results (Hodson ME et al. BMJ 1983; 286:1381-1383. )[PubMed]

1968 Schwarz V, Sutcliffe CH, Style PP. Some hazards of the sweat test. Arch Dis Child 1968; 43:695-701. [PubMed]
A detailed paper dealing with many practical aspects of the sweat test. Burns and blisters at the site of the electrodes were shown to be caused by penetration of acid generated electrolytically to the vicinity of the patient’s skin. Prevention of these and other errors are discussed in detail. In particular, the rapid evaporation which can occur from the collection pad resulting in up to a twofold increase in concentration of the sweat in 30 seconds – probably this is the major cause of over diagnosis from false high results.
For some years after the Fifties sweat tests were performed in many small laboratories on an occasional basis and mistakes were made – these were usually false positives and were due to evaporation leading to false high sweat electrolyte values (Smalley et al, 1978 below).

1972 Elliott RB. The effect of essential fatty acid on sweat sodium concentrations in cystic fibrosis. Aust Paediatr J 1972; 8:217
Prof. Bob Elliott and colleagues from Auckland, New Zealand published several papers showing improvement in the clinical state when children with CF were supplemented with medium chain triglycerides even to the extent of returning the sweat electrolytes to nearer normal values (also Elliott RB, Robinson PG. Arch Dis Child 1975; 50:75-78 below; Elliott RB. Pediatrics 1976; 57:474-479 below).
There was considerable discussion as to whether a disturbance of fatty acids resulted in an abnormality of prostaglandins. Rivers JA & Hassam AG suggested an abnormality of fatty acid metabolism such that there was a need for increased linoleic acid (Lancet 1975; ii: 642-643). Subsequent studies failed to substantiate their findings (Davidson GP et al. Aust Paediatr J 1978; 14:80-82; Chase et al. Pediatrics 1979; 59:428-432).

1973 MacLean WC, Tripp RW. Cystic fibrosis with oedema and falsely negative sweat test. J Pediatr 1973; 83:86-88. [PubMed]
An infant with CF, fed soya milk from age of 3 weeks, had oedema from 4 weeks. The sweat Cl values were 15 and 18 meq/l; later these had risen to 73 and 88 meq/l respectively. Subsequent reports of screened CF infants on normal milk feeds showed that, even in healthy CF infants, sweat tests may be relatively low and certainly less than 60 meq/l. (Massie J et al. Pediatr Pulmonol 2000; 29:452-456 below). So values over 30 meq/l would eventually be regarded as abnormal or requiring further investigation for a young infant. Also Lee PA, Roloff DW, Howatt WF. Hypoproteinemia and anaemia in infants with cystic fibrosis: Presenting symptom complex often misdiagnosed. JAMA 1974; 228: 585-588. Fifty one such infants are already described in literature. One third died and 14 had received soya milk feeds.

1975 Sarsfield JK, Davies JM. Negative sweat tests and cystic fibrosis. Arch Dis Child 1975; 50:463-466. [PubMed]
This is included as it was the first publication on CF from our general paediatric unit at Seacroft Hospital, Leeds where I had enlisted the out patient sister (senior nurse), dietitian and physiotherapist to join me in a small monthly CF clinic in 1975; there was an increasing interest in CF at the hospital. Dr John Davies, our senior paediatric registrar at the time, had developed stimulated pancreatic function tests on the lines recommended by Hadorn et al (1968 above), and reliable sweat tests had been available since the mid-Sixties performed by Mr. Alan Steele the biochemist; the latter service was used by many of the paediatricians in the Yorkshire Region since the mid-Sixties.
This report is of two brothers with chronic suppurative pulmonary disease; one had classical CF with complete pancreatic involvement and abnormal sweat tests. The other had incomplete pancreatic disease and repeatedly normal sweat tests. With these findings it was concluded that ”undue reliance on the sweat tests, especially when used for exclusion of cystic fibrosis, may be misplaced”.
Subsequently there have been many reports of patients with CF who had normal sweat tests some of whom have had unusual so-called “mild” mutations. Also, a more recent review of sweat tests in infants with CF diagnosed by neonatal screening, has shown that some infants with CF do indeed have a sweat test within the normal range for some time (Massie J et al. Pediatr Pulmonol 2000; 29:452).

1978 Smalley CA, Addy DP, Anderson CM. Does that child really have cystic fibrosis? Lancet 1978; ii: 415-417. [PubMed]
The first report from a major paediatric centre of children mistakenly diagnosed and treated as having cystic fibrosis. In this report, from Prof. Charlotte Anderson’s Birmingham CF unit, 14 referred children had an incorrect diagnosis of CF – 13 had previous sweat tests in other laboratories “where test not done very often”. In 5, detailed pancreatic function testing was normal. None had chest disease and only 2 had any gastrointestinal symptoms. The authors advised that “in the absence of typical clinical features of the disease, a diagnosis of cystic fibrosis should be made with extreme caution”.
This was a very important paper and prompted a number of reports on mistaken diagnosis (David TJ, Phillips BM. Overdiagnosis of cystic fibrosis. Lancet 1982; 2:1204-1206). The first 179 children, already diagnosed and treated as CF in general paediatric departments, who were referred to our Leeds CF Centre for Comprehensive Assessment during the Eighties, no less than 7 (4%) were found not to have CF – a sweat test to check the diagnosis was part of our assessment for which they were referred (Shaw NJ, Littlewood JM. Arch Dis Child 1987; 62:1271-1273 below). The over-diagnosis was usually the result of an uncritical acceptance of a positive sweat test result performed in a laboratory where the test was only performed occasionally.

1981 Webster Hl, Barlow WK. New approach to cystic fibrosis diagnosis by use of an improved sweat-induction/collection system and osmometry. Clin Chem 1981; 27:385-387. [PubMed]
First use of osmometry of the sweat to distinguish people with CF from controls. The method was validated in a number of subsequent studies (Kirk JM et al. 1983 below) but never became widely adopted or replaced the standard sweat test..
First use of osmometry of the sweat to distinguish people with CF from controls. The method was validated in a number of subsequent studies (Kirk JM et al. 1983 below) but never became widely adopted or replaced the standard sweat test..

1983 Kirk JM, Adams A, Westwood A, McCrae WM. Measurement of osmolality and sodium concentration in heated cup sweat collections for investigation of cystic fibrosis. Ann Clin Biochem 1983; 20:369-373. [PubMed]
A study from Edinburgh of a new system (Wescor) for sweat collection and analysis with respect to its suitability for the investigation of children suspected to have cystic fibrosis. The effects of iontophoresis current sweat collection time, sweat storage and analysis were examined, and as a result the technique was modified to allow collection and storage of sufficient sweat for sodium and potassium as well as osmolality assays in 10-20 minutes. The small electrodes and speed of the procedure made it practical for use with small children, with a reproducibility of 13-24% (coefficient of variation for whole procedure (also Carter EP et al. 1984; Webster & Barlow, 1981). Most centres did not employ this system.

2007 LeGrys VA, Yankaskas JR, Quittell LM, Marshall BC, Mogayzel PJ Jr. Cystic Fibrosis Foundation. Diagnostic sweat testing: the Cystic Fibrosis Foundation guidelines. J Pediatr 2007; 151:85-89. [PubMed]
The most recent guidelines from the CF Foundation. Similar guidelines have been published in the UK (Report from the Multi-Disciplinary Working Group. Anne Green Nov. 2003) and other countries so important is it that sweat tests are accurate to avoid the clinical disasters of mistaken diagnoses. Usually the mistakes are over-diagnosis due to the uncritical acceptance by the clinician of an false high sweat test (also Smalley et al, 1978 above; Shaw & Littlewood, 1987 above).

Green A. Kirk J. Guidelines Development Group. Guidelines for the performance of the sweat test for the diagnosis of cystic fibrosis. Ann Clin Biochem 2007; 44(Pt 1):25-34.[PubMed]. A multidisciplinary group (representing various professional bodies and supported by the Cystic Fibrosis Trust) has developed evidence-based guidelines for the performance of the sweat test in the UK. The guidelines cover patient information, subject suitability, sweat collection, sweat analysis, quality, interpretation of results, and responsibility for testing and training. The guidelines were produced following a detailed literature search by the process described by the Royal College of Paediatrics and Child Health (RCPCH), using the Scottish Intercollegiate Guidelines Network 1 (SIGN 1) criteria to grade the evidence. Recommendations are graded A, B, or C, depending on the level of evidence. The grade B recommendations (there were no grade A recommendations) were subsequently appraised and endorsed as part of the RCPCH process, according to Appraisal of Guidelines for Research and Evaluation in Europe (AGREE). The recommendations are summarized in tabular form representing the final version incorporating the comments from the appraisal process.

Both the appraisal comments and the full evidence base can be found on www.rcpch.ac.uk/publications/clinical_docs.html. The full guidelines can also be found on http://www.ukneqas.org.uk/guidelines.htm.

2008 Desax MC, Ammann RA, Hammer J, Schoeni MH, Barben J. Swiss Paediatric Respiratory Research Group. Nanoduct sweat testing for rapid diagnosis in newborns, infants and children with cystic fibrosis. Eur J Pediatr 2008; 167:299-304. [PubMed]
Determination of chloride concentration in sweat is the current diagnostic gold standard for CF. Nanoduct is a new analyzing system measuring conductivity which requires only 3 microliters of sweat and gives results within 30 minutes. The authors concluded that the Nanoduct test is a reliable diagnostic tool for CF diagnosis: It has a failure rate comparable to other sweat tests and can be used as a simple bedside test for fast and reliable exclusion, diagnosis or suspicion of CF. In cases with borderline conductivity (60-80 mmol/L) other additional methods (determination of chloride and genotyping) are indicated.

2009 Goubau C, Wilschanski M, Skalicka V, Lebecque P, Southern KW, Sermet I, Munck A, Derichs N, Middleton PG, Hjelte L, Padoan R, Vasar M, De Boeck K. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax 2009; 64:683-691. [PubMed] Patients with intermediate sweat chloride values in whom either additional CF diagnostic test was abnormal were compared with subjects in whom this was not the case and patients with classic CF. The phenotypic features of four groups were compared: 59 patients with CFTR dysfunction, 46 with an intermediate sweat chloride concentration but no evidence of CFTR dysfunction (CF unlikely), 103 patients with CF and pancreatic sufficiency (CF-PS) and 62 with CF and pancreatic insufficiency (CF-PI). The CFTR dysfunction group had more lower respiratory tract infections (p = 0.01), more isolation of CF pathogens (p<0.001) and clubbing (p = 0.001) than the CF unlikely group, but less frequent respiratory tract infections with CF pathogens than the CF-PS group (p = 0.05). Patients in the CF-PS group had a milder phenotype than those with PI. Many features showed stepwise changes through the patient groups. The authors concluded that patients with intermediate sweat chloride values and two CFTR mutations or an abnormal NPD measurement have a CF-like phenotype compatible with CFTR dysfunction and, as a group, differ phenotypically from patients with intermediate sweat chloride values in whom further CF diagnostic tests are normal as well as from CF-PS and CF-PI patients.

Although these conclusions seem obvious there are helpful when considering patients with a dubious diagnosis.