Cystic fibrosis in adults: the unsuspected pulmonary diagnosis Anthony J. Nolan, mb,
frcp[c]
The clinical spectrum of cystic fibrosis is insufficiently appreciated. This diseae may occur in adolescents or adults who had minimal or no symptoms in childhood. In three patients the diagnosis was made on the basis of respiratory disease
Cystic fibrosis is a diffuse exocrinopathy whose clinical characteristics were first fully described by Anderson1 in 1938; because these characteristics were related mainly to its effect on pancreatic function the disease became known as "fibrocystic disease of the (including bronchiectasis, pneumonia pancreas". At that time it was con¬ and chronic bronchitis), a family sidered a rare disease affecting only history of respiratory disease, and infants, manifesting itself mainly by elevated concentrations of electrolytes decreased pancreatic function, and in the sweat. Two of the patients being almost uniformly fatal. We now had pancreatic insufficiency, but this know that cystic fibrosis is one of the feature was not considered necessary commonest causes of mortality and for the diagnosis. It is important to morbidity in infancy and childhood. make the diagnosis of cystic fibrosis Moreover, death is caused much more in affected adults in order to prescribe commonly by involvement of the res¬ appropriate therapy, avoid unnecessary piratory system than by gastrointestinal operations, anticipate complications complications. Indeed, 10 to 15% of that are not common to other respiratory patients with cystic fibrosis have nor¬ diseases, provide genetic counselling mal pancreatic function,2 so that the and initiate appropriate screening clinical hallmark of cystic fibrosis is procedures to detect the disease in now disease of the respiratory system. close relatives. Although there are several reports of the diagnosis being made in adults,3"12 most of these patients had symptoms in Le spectre clinique de la fibrose kystique n'est pas suffisamment connu. childhood suggestive of the disease. It is not sufficiently appreciated by physi¬ Cette pathologie peut survenir chez cians practising adult medicine that I'adolescent ou chez I'adulte qui, dans I'enfance, n'avait pas ou guere presente cystic fibrosis may appear in adoles¬
de symptdmes. Chez trois malades on a pu etablir le diagnostic a partir de
pneumopathies (dont bronchiectasie, pneumonie et bronchite chronique), d'antecedents familiaux de maladies respiratoires, et de concentrations excessives d'electrolytes dans la
Chez deux de ces malades une insuffisance pancreatique etait presente, mais cette deficience n'a pas ete jugee necessaire pour etablir le diagnostic. Chez I'adulte affecte il est important de faire le diagnostic de la fibrose kystique, en vue de prescrire un traitement approprie, d'eviter des operations inutiles, de prevoir des complications qui ne sont pas le propre d'autres pneumopathies, de fournir des conseils genetiques et de prendre les mesures voulues pour deceler la maladie chez des parents proches. sueur.
From the medical service, San Francisco General Hospital, and the department of medicine and the Cardiovascular Research Institute, University of California, San Francisco This work was supported by the BC Tuberculosis-Christmas Seal Society and the Medical Research Council of Canada. The paper was presented at the first joint meeting of the Canadian and American thoracic societies at Montreal, May 21, 1975. Reprint requests to: Dr. A.J. Nolan, Ste. 406A, 402 East Columbia St., New Westminster, BC V3L 3X1
cents
or
adults who have had minimal
symptoms in childhood. This report describes three patients
or no
in whom the diagnosis of cystic fibrosis made in adult life; none of them had the common symptoms of cystic fibrosis in childhood. These patients were referred to the adult chest service of the University of California Medical Center at San Francisco. The diagnosis was made by the author in patients 1 and 2 and by another physician in pa¬ tient 3. All sweat electrolyte estimations were performed in the same laboratory by the pilocarpine iontophoresis meth¬ od.13 Quantitative immunoglobulin de¬ terminations yielded normal results in all patients. The clinical features are summarized in Table I. was
ticipated in physical activities at school with no complaints. At the age of 18 he had had heat stroke several times during his basic army train¬ ing in a hot humid environment; he had also noted salt deposition on his skin after sweating. Shortly thereafter, left lower lobe pneumonia had developed, with wheezing and a productive cough, which improved slowly with appropriate treat¬ ment. Values from two sweat chloride estimations performed during military serv¬ ice were stated to be "high". After dis¬ charge he had had frequent episodes of wheezing, recurrent respiratory tract infections and progressive dyspnea on exertion. He also complained of frequent abdominal discomfort and "gas pains", most pronounced after meals, and frequent diarrhea over the year before the consulta¬ tion. Sweat electrolyte estimation in this laboratory showed a sodium value of 143 mmol// (normal range, 8 to 55 mmol//) and a chloride value of 138 mmol// (nor¬ mal range, 9 to 56 mmol//)-
His brother had died of bronchiectasis of 18. He was well developed and had no ab¬ normal physical findings except for mild thoracolumbar scoliosis. A chest radiograph (Fig. 1) showed a semicircular density in the right upper lobe, which cleared gradually with ther¬ apy. There was radiologic evidence of chronic sinusitis. Sputum culture grew Hemophilus influenzae and Pseudomonas at the age
Table I.Clinical features of three adults with cystic fibrosis
Case reports Patient 1
A 26-year-old electrician was seen in consultation because of dyspnea on exertion. Episodes of vomiting during the first 6 months of his life had responded to the elimination of milk and milk products from his diet. His childhood history was otherwise unremarkable and he had par-
142 CMA JOURNAL/JANUARY 24, 1976/VOL. 114
absent; + present; | increased; decreased; NI not investigated. *Normal range, 9 to 56 mmol//. =
i
=
=
=
=
aeruginosa. Pulmonary function
tests per¬
formed after clinical and radiologic re¬ covery showed moderately severe airway obstruction with a good response to bron¬ chodilator inhalation (Table II). A 72-hour stool collection, when his dietary intake of fat was 100 g daily, contained 45 g of fat (normal, < 15 g) and 8.2 g of total fecal nitrogen (normal, < 3 g). A secretin stimulation test showed a decreased volume of pancreatic secretion and decreased bicarbonate concentration in the secretions. A rectal biopsy showed normal rectal mucosa and a skin biopsy from the forearm showed morphologically normal sweat glands. A semen sample could not be obtained for analysis. His symptoms resolved on treatment
Table II.Results of function tests
pulmonary Patient no.
Test Vital capacity, % of predicted Residual volume (RV), % of predicted 122 Total lung capacity (TLC), %of predicted 97
1 102
98
82
111
125
100
93
RV/TLC, % observed/ % predicted 34/27 26/25 35/30 FEVi*/FVCt,%observed/% 69/80 77/85 70/84 predicted 152 113 125 DlCOJ, % of predicted *FEVi forced expiratory volume in 1 second. fFVC forced vital capacity. jDlCO single-breath carbon monoxide diffusing capacity (ml/min- mm Hg). =
=
=
FIG. 1.Patient 1:
density abutting
on
FIG. 2.Patient 1: after radiograph in
upper lobe minor fissure.
Right
with tetracycline, physical therapy and pancreatic replacement therapy. Contrary to instructions he discontinued postural drainage after discharge and was readmitted 3 months later with right middle lobe atelectasis and pneumonia (Fig. 2), which responded very slowly to therapy. Sputum culture on this occasion grew P. aeruginosa and Staphylococcus aureus. No spermatozoa could be seen in a sample of ejaculate less than 0.1 ml in volume.
Patient 2
19-year-old junior college student was in consultation because of a produc¬ tive cough. At the age of 5 he had undergone tonsillectomy and adenoidectomy, and cobalt irradiation for multiple episodes of pu¬ A
seen
rulent otitis media which resolved there¬ after. Between the ages of 5 and 16 he was well, apart from frequent episodes of vague dyspepsia following meals. From the age of 16 he had had a cough productive of increasing amounts of foul green sputum. He had severe night sweats, an almost continuous postnasal drip and frequent upper respiratory tract infections. He had no wheezing or dysp¬ nea and played many sports competitively at college. One month before the consulta¬ tion a sputum culture had grown many colonies of coagulase-positive S. aureus. Bronchograms performed at that time were reported as showing "bilateral upper lobe cylindrical bronchiectasis of moderate degree and changes in the remainder of the bronchi consistent with chronic bron¬ chitis"; resective lung surgery was dis¬ cussed. He also complained of vague ab¬ dominal cramps following meals. His paternal great-grandmother had died of "asthma" at the age of 40 and his paternal grandmother had suffered from asthma, sinusitis, a productive cough and abdominal complaints all her life. His 65year-old nonsmoking maternal grandfather had "chronic bronchitis". His 4-year-old sister had recurrent upper respiratory tract infections. He was well developed and had no ab¬ normal physical findings. A chest radiograph showed patchy infiltrative disease in the right upper lobe (Fig. 3). Radiographs of the paranasal sinuses showed acute and chronic sinusitis. Pulmonary function testing showed mild
Collapse of right middle lobe with consolidation 3 months Fig. 1 was made.
airway obstruction (Table II) and some maldistribution of ventilation. Sweat elec¬ trolyte estimation showed a sodium value of 119 mmol// and a chloride value of 116 mmol//. A fecal smear was strongly positive for fat (Sudan III stain; and a duodenal aspi¬ rate was negative for trypsin. The patient could not produce a sample of semen for
analysis. Antral washings relieved his postnasal drip and he reported disappearance of his abdominal discomfort with pancreatic en¬ zyme replacement therapy (Pancrelipase, Cotazym). He was instructed in hydration and postural drainage and started on a suitable antibiotic regimen. His 4-year-old sister had sweat sodium
and chloride values of 124 mmol//. His 2-month-old brother had a sweat sodium value of 53 mmol// and a sweat chloride value of 40 mmol//, and repeat testing showed similar values. Other members of his family had values for sweat electrolytes well below the upper limits of normal. Patient 3 As a child this 20-year-old anthropology student had had recurrent rhinorrhea dur¬ ing the ragweed season. When he was 13 a
chronic cough, diagnosed
as
"sinusitis",
had developed. Between the ages of 15 and 20 he had had an average of six respira¬ tory tract infections per year, consisting of a cough productive of purulent sputum, wheezing, dyspnea on exertion, chills and fever. These episodes responded rapidly to antibiotics but tended to recur when anti¬ biotics were stopped. Sputum cultures at various times grew Klebsiella pneumoniae and S. aureus. Finger clubbing was first noted at the age of 18. He had no symp¬ toms tem.
referable to the gastrointestinal sys¬
His maternal grandmother had had a chronic productive cough all her life and had died at the age of 55 with a diagnosis of tuberculosis. He was well developed and had club¬ bing of the fingers and toes but no other important physical abnormalities. A chest radiograph showed a diffuse interstitial process in both lungs, most pronounced in the upper lobes. Magnifica¬ tion views showed endobronchial thicken¬ ing throughout both lung fields. Radio¬ graphs of the sinuses showed acute and
FIG. 3.Patient 2: right upper lobe.
Patchy infiltration in
CMA JOURNAL/JANUARY 24, 1976/VOL. 114 143
chronic sinusitis.
Sputum culture grew aureus and a mod¬ erate number of colonies of P. aeruginosa. Pulmonary function testing showed evid¬ ence of hyperinflation and airway obstruc¬ tion (Table II). Estimation of sweat electrolytes showed a sodium value of 118 numerous
colonies of S.
mmol// and a chloride value of 112 mmol//. Fat content of a 72-hour stool collection was slightly high, at 18.8 g, but trypsin was present in stool to a dilution of 1:80. Despite repeated courses of antibiotics sputum cultures continued to grow S. aureus and P. aeruginosa. Eight days after discharge he was readmitted with acute pancreatitis, which rapidly responded to conventional ther¬ apy. His sputum culture again grew P. aeruginosa and S. aureus. This patient failed to keep outpatient appointments and was lost to follow-up. However, correspondence from other hos¬ pitals indicated that his respiratory prob¬ lems were continuing.
Discussion The prognosis for patients with cystic fibrosis was greatly improved by the introduction of antibiotics:14 now more and more such patients survive into adult life.2,15 Adult patients with cystic fibrosis appear to fail into one of two
categories:
1. Those with moderate or severe respiratory disease who have had symp¬
toms typical of cystic fibrosis since in¬ fancy or childhood. For most of these patients the diagnosis is made in early life and they are often cared for by their pediatrician even into adult life, the internist seeing them only in con¬
sultation. 2. Those with mild
or
moderate
gastrointestinal disease whose symptoms in childhood were so mild that diagnosis was not made till later in life unless there was a family history of the disease, or who had no symptoms. These patients are encount¬ ered by the family physician or internist and present a challenge to practitioners pulmonary
or
of internal medicine.16 The patients described here fail into the second category and are remark¬ able for the lack of respiratory symp¬ toms in their early life. The absence of finger clubbing in two of these patients, in contrast to its presence in adult pa¬ tients, is consistent with the late onset of respiratory disease.7,8 The early med¬ ical history of these patients included ear infections, manifestations of allergy and vague abdominal complaints, none of which were sufficiently severe to cause anxiety to the patient or his parents. Recurrent otitis media (pa¬ tient 2) is a complication of cystic fi¬ brosis, and hearing loss and speechlanguage deficiency have been reported in children with cystic fibrosis and re¬
current otitis media.17 Nevertheless, otitis media is such a common disorder of childhood and responded so well to therapy in patient 2 that its relation to cystic fibrosis was understandably not considered at the time. Vague epi¬ sodes of abdominal pain are frequent in patients with cystic fibrosis and have been ascribed to transient fecal impaction or pancreatitis.12'18 Patient 2 gave
a history of mild dyspepsia from about the age of 6. These symptoms devel¬ oped in patient 1 much later in life. Results of pulmonary function tests in these patients were fairly typical of those for mild to moderate involvement of the lung by the disease.19 In these three cases the diagnosis was first suggested by the development of respiratory symptoms in a patient with a family history of respiratory disease. The diagnosis was confirmed by the finding of elevated sweat electrolyte values. Pulmonary infections due to S. aureus or P. aeruginosa, or both, oc¬ curred at some time in each of these patients and is characteristic of cystic fibrosis. Pancreatic function was insuf¬ ficient in the two patients in whom it was investigated; however, this abnor¬ mality is not necessary for the diag¬ nosis2 and in children it frequently improves as they get older. Therefore, the combination of a suggestive family history in a patient with respiratory symptoms, especially when he is sus¬ ceptible to infection with S. aureus or P. aeruginosa or both, should prompt the physician to investigate the concen¬ tration of sodium and chloride in the patient's sweat. Sweat tests should be performed more than once because false-negative results are found.20 While there is some disagreement concerning the normal concentrations of sweat electrolytes in adults,21 the values in these three patients would be accepted by most workers as indicative of cystic fibrosis in the adult. The question of the importance of early diagnosis of cystic fibrosis in chil¬ dren has recently been debated, because methods of screening the population for cystic fibrosis will probably be available in the near future. There is good evidence that mortality and mor¬ bidity in children are reduced and sur¬ vival is prolonged by early and inten¬ sive therapy in a centre specializing in treatment of cystic fibrosis.14,15 How¬ ever, it is less clear whether diagnosis when the child is still asymptomatic alters the prognosis.22'24 All of these studies refer to patients in whom the diagnosis was made early in life and not to adults. Distinguishing the adult patient with
a predominantly genetic disease, cystic fibrosis, from the patient with respira¬
tory disease due mainly
144 CMA JOURNAL/JANUARY 24, 1976/VOL. 114
to environ¬
mental
causes
is
lowing reasons:
important for the fol¬
Failure to realize that a patient cystic fibrosis may result in respira¬ tory infections being treated with inappropriate antibiotics. Respiratory in¬ fections in such patients are frequently .
has
caused by S. aureus and P. aeruginosa, and the latter is found more frequently after inappropriate antibiotic therapy. Moreover, in severely ill patients there is a high incidence of infection by atypical "mucoid" strains of P. aerugi¬ nosa, which appear to be much more invasive and less sensitive to antibiotics than the more typical "rough" organ¬ isms.25 Serum from a patient with cystic fibrosis may contain a factor that in¬ hibits preferentially the phagocytosis of P. aeruginosa by alveolar macro¬
phages.26
. Consideration of resective lung surgery may be considerably modified when the progressive nature of the dis¬ order is recognized. Such surgery had been discussed for patient 2 because of bronchiectasis before referral. Also, the demonstration of "meconium ileus equivalent" in adult patients with cystic fibrosis18'27 should prompt surgeons to try conservative therapy before performing laparotomy when these pa¬ tients have an intestinal obstruction.28'29 . The complications of cystic fibro¬ sis differ in many respects from those of other respiratory diseases. Diabetes mellitus is more frequent in patients with cystic fibrosis than in those with other chronic respiratory diseases.30 Liver dysfunction in a patient with cys¬ tic fibrosis could well be due to the diffuse nature of the underlying disease rather than to a second pathologie pro¬
cess.18 Gastrointestinal complications and decreased fertility have been re¬ ported. Such complications can be anti¬ cipated and sometimes prevented if the nature of the problem is recognized
(Table III).
. It is important that the patient know his or her state of fertility. While reports have appeared of males with cystic fibrosis who appeared to be fertile,11 the majority of males with the disease are infertile.31 While females with the disease are less fertile, they are often capable of childbearing. How¬ ever, they have a much higher incid¬ ence of obstetric complications. The pregnancy itself may initiate rapid decompensation in their cardiopulmonary status and may, in fact, contribute to death in the early postpartum period.32 Since the severity of such complications is related to the degree of pulmonary disease, we would not expect a noticeable increase in the complications of pregnancy in this group of patients. However, because the woman with cys¬ tic fibrosis has a much greater chance
WW, CUGELL DW, ZELKOWITZ PS, et al: Cystic fibrosis of the pancreas; a comparison of the pulmonary manifestations in children and young adults. Chest 59: 306, 1971 TAussio LM, LosEcic CC, Di SANT'AGNE5E PA, et al: Fertility in males with cystic fibrosis. N Engi I Med 287: 586, 1972 GRACEY M, ANDERSON CM: Cystic fibrosis of the pancreas in adolescence and adulthood. Australas Ann Med 18: 91, 1969 GiBsoN LE, COOKE RE: A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilising pilocarpine by iontophoresis. Pediatrics 23: 545, 1959 MEARNS MB: Treatment and prevention of pulmonary complications of cystic fibrosis in early childhood. Arch Dis Child 47: 5, 1972 SHWACHMAN H, REDMOND A, KNAW KT: Studies in cystic fibrosis. Report of 130 patients diagnosed under 3 months of age over a 20 year period. Pediatrics 46: 335, 1970 POGUE RE, WARWICK WJ: Cystic fibrosis. A new challenge to internal medicine. Minn Med 52: 1551, 1969 FoRcucci RA, STARK EW: Hearing loss, speech-language and cystic fibrosis. Arch Otolaryngol 96: 361, 1972 KOPEL FB: Gastrointestinal manifestations of cystic fibrosis; a review. Gastroenterology 62: 483. 1972 RAms DV, MACKLEM PT, CHRIsTIE RV: Respiratory Function in Disease, second ed, Philadelphia, Saunders, 1971, p 240 WARWICK WJ: How cystic fibrosis can be confused with chronic bronchitis and bronchial asthma. Minn Med 52: 1476, 1969 SEKELJ P, BELMONTE M, RASMUSSEN K, et al: Survey of electrolytes of unstimulated sweat from the hand in normal and diseased adults. Am Rev Respir Dis 108: 603, 1973 LAWSON D: Cystic fibrosis: assessing the effects of treatment. Arch Dis Child 47: 1, 1972 WARWICK WJ, POGUE RE: Computer studies in cystic fibrosis, in Proceedings of the Sih International Cystic Fibrosis Conference, edited by LAWSON D, London, Cystic Fibrosis Trust, 1969, p 320 BRIMBLECOMBE FSW, CHAMBERLAIN J: Screening for cystic fibrosis. Lancet 2: 1428, 1973 DOGGErIT RG, HAlutisoN GM: Pseudomonas aeruginosa. Immune status jn patients with cystic fibrosis. Infect Immun 6: 628, 1972 BOXERBAUM B, KAGUMBA M, MArrHaWs LM: Selective inhibition of phagocytic activity of rabbit alveolar macrophages by cystic fibrosis serum. Am Rev Respir Dis 108: 777, 1973 IBAcH EG: Meconium ileus equivalent in an adult patient. Med I Aust 1: 268, 1968 NOBLETT HR: Treatment of uncomplicated meconium ileus by Gastrografin enema: a preliminary report. I Pediatr Surg 4: 190, 1969
Table Ill-Some complications of cystic fibrosis in adults Respiratory system Nasal polyposis, sinusitis T tendency for viral infections to lead to bacterial pneumonias Bronchiectasis, chronic bronchitis Atelectasis, pneumonia Pneumothorax, empyema
10. ADDINOTON
Gastrointestinal system Intermittent abdominal cramps and pains Meconium ileus equivalent Duodenal ulcer Volvulus and intussusception Pancreatitis Hepatic (biliary) cirrhosis, portal hypertension, hypersplenism, etc.
14.
Genitourinary system Sterility in males, .L fertility in females T morbidity and mortality in pregnancy I fetal mortality Other Heat stroke, Na. depletion, leading to shock if ill Diabetes mellitus Pulmonary hypertension and cor pulmonale Polycythemia, hemosiderosis
11.
12. 13.
15.
16. 17. 18. 19. 20. 21.
22.
of having a similarly affected child, advice on contraception should be offered to all women with cystic fibrosis irrespective of severity of their disease.33 0 Making the diagnosis will initiate appropriate screening of siblings and children and so allow early diagnosis of the disease in near relatives. The clinical spectrum of cystic fibrosis is insufficiently appreciated. As Warwick20 has commented, "If a patient has asthma or chronic bronchitis and has never had a sweat test, it would be sheer medical folly to perpetuate an incorrect diagnosis by failing to do a sweat test because the patient was in his late teens or twenties." I thank John F. Murray, MD and Warren Gold, MD for helpful comments during the preparation of this paper and for permission to discuss patient 3.
References 1. ANDERSON DH: Cystic fibrosis of the pancreas and its relation to celiac disease. Am J Dis Child 56: 344, 1938 2. SCHWACHMAN H, KULCZYCKI LL: Long term study of 105 patients with cystic fibrosis. Am J Dis Child 96: 6, 1958 3. CECE JD, HENRY JP, ToiGo A: Pancreatic cystic fibrosis in an adult. JAMA 181: 31, 1962 4. POLGAR G, DENTON R: Cystic fibrosis in adults; studies of pulmonary function and some physical properties of bronchial mucus. Am Rev Respir Dis 85: 319, 1962 5. ANDERSON EG, LA5ZLO G, BROWN HM: A case of mucoviscidosis in an adult. Br J Dis Chest 59: 173, 1965 6. COArss EO: Characteristics of cystic fibrosis in adults; a report of 7 patients. Dis Chest 49: 195. 1966 7. TOMASHEFSKI iF, CHRISToFoRIDIS AJ, ARDULLAK AK: Cystic fibrosis in young adults; an overlooked diagnosis with emphasis on pulmonary function and radiological patterns. Chest 57: 28. 1970 8. GRAND Ri, TALAMO RC, DI SANT'AGNESE PA, et al: Pregnancy in cystic fibrosis of the pancreas. JAMA 195: 993. 1966 9. JONES JS: Adult cystic fibrosis (mucoviscidosis). Br I Dis Chest 64: 25, 1970
23.
24.
25. 26. 27. 28.
29. LILLIEBRIDGE CB, DOCTOR JM, EIDELMAN 5: Prophylaxis of meconium ileus equivalent with N-acetyl cysteine. I Pediatr 71: 887,
1967 30. ROSAN RC, SHWACHMAN H, KULCZYCKI LL:
Diabetes mellitus and cystic fibrosis of the pancreas. Am I Dis Child 104: 625, 1962
31. KAPLAN E, SCHWACHMAN H, PERLMUTI-ITER AD,
et al: Reproductive failure in males with cystic fibrosis. N Engi I Med 279: 65, 1968 32. LARSEN JW: Cystic fibrosis and pregnancy. Obstet Gynecol 39: 880, 1972 33. ANDERSON VE: Genetic counselling for parents. Minn Med 52: 1570, 1969
DISSEMINATED HISTOPLASMOSJS Continued from page 141 16. FUDENBERG HH, LEvIN AS, SPITLER LE, et al: The therapeutic uses of transfer factor. Hosp Practice 95, 1974 17. WHrrcOMa ME, ROcIcs.iN RE: Transfer factor therapy in a patient with progressive primary tuberculosis. Ann Intern Med 79: 161, 1973 18. CATANZARO A, SPITLER L, MOSER. KM: Immunotherapy of coccidioidomycosis. I Clin
Invest 54: 690, 1974
19. KIRKPATRICK
CH,
WILSON
WEC,
TALMAGE
DW: Immunologic studies in human organ transplantation. IExp Med 119: 727, 1964
20. JENSEN K, PATNODE RA, TOWNSLEY HC, et al: Multiple passive transfer of the delayed type of hypersensitivity in humans. Am Rev
Resp Dis 85: 373, 1962
21. PAQIJE RE, KNISKERN P1, DRAY 5, et al:
Transfer of the cell-migration inhibition correlate of delayed hypersensitivity in humans with nondialyzable components of leucocyte lysates from humans sensitized to histoplasmin and coccidioidin. Cell Immunol 6: 368, 1973 22. THOR DE, DRAY 5: The cell-migration-inhibition correlate of delayed hypersensitivity. I Immunol 101: 469, 1968
Apresoline
the unique "ADD ON" antihypertensive INDICATIONS: Various forms of hypertension: fixed essential hypertension, whether of benign or malignant character; hypertension associated with acute and chronic glomerulonephrit is; nephrosclerosis; hypertensive toxemias of pregnancy, pre-eclampsia, and eclampsia. DOSAGE: Hypertension: Orally: In general after initiating therapy gradually increase dosage, adjusting according to individual response. As a single agent, initially 10mg, four times daily increasing slowly to a maximum practical dosage of 200mg daily. In combination with other hypotensive agents, lower dosages of APRESOLINE will be appropriate. Parenterally: When there is urgent need, therapy in the hospitalized patient may be initiated intravenously or intramuscularly. Usual dose is 20 to 40 mg, repeated as necessary. Certain patients, especially those with marked renal damage, may require a lower dose. Pressure may begin to fall within a few minutes after injection, with an average maximal decrease occurring in 10 to 80 minutes. Most patients can be transferred to oral APRESOLINE within 24 to 48 hours. Toxemia of Pregnancy: a) Early toxemia and hypertension of pregnancy: One 10-mg tablet orally 4 times daily, slowly increasing the dosage up to 400 mg per day, or until a therapeutic result is obtained. b) Late toxemia and pre-eclampsia: Give 20 to 40 mg intramuscularly, or slowly by direct intravenous injection or infusion. Repeat as necessary. SIDE EFFECTS: Tachycardia, headache, palpitation, dizziness, weakness, nausea, vomiting, postural hypoterision, numbness and tingling of the extremities, flushing, nasal congestion, lachrymation, conjunctival injection, dyspnea, anginal symptoms, rash, drug fever, reduction in hemoglobin and red cell count, giant urticaria, and a lupus-like syndrome (arthralgia) in some cases following administration for long periods. CAUTIONS: Use cautiously in the presence of advanced renal damage and recent coronary or cerebral ischemia. APRESOLINE may potentiate the narcotic effects of barbiturates and alcohol. Peripheral neuritis evidenced by paresthesias, numbness and tingling has been observed. Published evidence suggests an anti-pyridoxine effect and addition of pyridoxine to the regimen if symptoms develop. OVERDOSAGE: Symptoms: Hypotension and tachycardia. Treatment: Gastric lavage or, in the absence of coma, emetics. In the presence of hypotension, cautiously give norepinephrine (intravenously) or ephedrine to raise the blood pressure without increasing tachycardia. Avoid epinephrine. General supportive measures include intravenous fluids, external heat and elevation of foot of bed. SUPPLIED: All forms contain hydralazine hydrochlorideTablets of 10mg (yellow, scored); bottles of lOOTablets of 25mg (blue, coated); bottles of 100 and 500 Tablets of 50mg (pink, coated); bottles of 100 and 500. Ampoules of 1 ml aqueous solution containing 20 mg; boxes of 10.
CIBA DORVAL, QUEBEC
C-5003
CMA JOURNAL/JANUARY 24, 1976/VOL. 114 145
frcp[c]
The clinical spectrum of cystic fibrosis is insufficiently appreciated. This diseae may occur in adolescents or adults who had minimal or no symptoms in childhood. In three patients the diagnosis was made on the basis of respiratory disease
Cystic fibrosis is a diffuse exocrinopathy whose clinical characteristics were first fully described by Anderson1 in 1938; because these characteristics were related mainly to its effect on pancreatic function the disease became known as "fibrocystic disease of the (including bronchiectasis, pneumonia pancreas". At that time it was con¬ and chronic bronchitis), a family sidered a rare disease affecting only history of respiratory disease, and infants, manifesting itself mainly by elevated concentrations of electrolytes decreased pancreatic function, and in the sweat. Two of the patients being almost uniformly fatal. We now had pancreatic insufficiency, but this know that cystic fibrosis is one of the feature was not considered necessary commonest causes of mortality and for the diagnosis. It is important to morbidity in infancy and childhood. make the diagnosis of cystic fibrosis Moreover, death is caused much more in affected adults in order to prescribe commonly by involvement of the res¬ appropriate therapy, avoid unnecessary piratory system than by gastrointestinal operations, anticipate complications complications. Indeed, 10 to 15% of that are not common to other respiratory patients with cystic fibrosis have nor¬ diseases, provide genetic counselling mal pancreatic function,2 so that the and initiate appropriate screening clinical hallmark of cystic fibrosis is procedures to detect the disease in now disease of the respiratory system. close relatives. Although there are several reports of the diagnosis being made in adults,3"12 most of these patients had symptoms in Le spectre clinique de la fibrose kystique n'est pas suffisamment connu. childhood suggestive of the disease. It is not sufficiently appreciated by physi¬ Cette pathologie peut survenir chez cians practising adult medicine that I'adolescent ou chez I'adulte qui, dans I'enfance, n'avait pas ou guere presente cystic fibrosis may appear in adoles¬
de symptdmes. Chez trois malades on a pu etablir le diagnostic a partir de
pneumopathies (dont bronchiectasie, pneumonie et bronchite chronique), d'antecedents familiaux de maladies respiratoires, et de concentrations excessives d'electrolytes dans la
Chez deux de ces malades une insuffisance pancreatique etait presente, mais cette deficience n'a pas ete jugee necessaire pour etablir le diagnostic. Chez I'adulte affecte il est important de faire le diagnostic de la fibrose kystique, en vue de prescrire un traitement approprie, d'eviter des operations inutiles, de prevoir des complications qui ne sont pas le propre d'autres pneumopathies, de fournir des conseils genetiques et de prendre les mesures voulues pour deceler la maladie chez des parents proches. sueur.
From the medical service, San Francisco General Hospital, and the department of medicine and the Cardiovascular Research Institute, University of California, San Francisco This work was supported by the BC Tuberculosis-Christmas Seal Society and the Medical Research Council of Canada. The paper was presented at the first joint meeting of the Canadian and American thoracic societies at Montreal, May 21, 1975. Reprint requests to: Dr. A.J. Nolan, Ste. 406A, 402 East Columbia St., New Westminster, BC V3L 3X1
cents
or
adults who have had minimal
symptoms in childhood. This report describes three patients
or no
in whom the diagnosis of cystic fibrosis made in adult life; none of them had the common symptoms of cystic fibrosis in childhood. These patients were referred to the adult chest service of the University of California Medical Center at San Francisco. The diagnosis was made by the author in patients 1 and 2 and by another physician in pa¬ tient 3. All sweat electrolyte estimations were performed in the same laboratory by the pilocarpine iontophoresis meth¬ od.13 Quantitative immunoglobulin de¬ terminations yielded normal results in all patients. The clinical features are summarized in Table I. was
ticipated in physical activities at school with no complaints. At the age of 18 he had had heat stroke several times during his basic army train¬ ing in a hot humid environment; he had also noted salt deposition on his skin after sweating. Shortly thereafter, left lower lobe pneumonia had developed, with wheezing and a productive cough, which improved slowly with appropriate treat¬ ment. Values from two sweat chloride estimations performed during military serv¬ ice were stated to be "high". After dis¬ charge he had had frequent episodes of wheezing, recurrent respiratory tract infections and progressive dyspnea on exertion. He also complained of frequent abdominal discomfort and "gas pains", most pronounced after meals, and frequent diarrhea over the year before the consulta¬ tion. Sweat electrolyte estimation in this laboratory showed a sodium value of 143 mmol// (normal range, 8 to 55 mmol//) and a chloride value of 138 mmol// (nor¬ mal range, 9 to 56 mmol//)-
His brother had died of bronchiectasis of 18. He was well developed and had no ab¬ normal physical findings except for mild thoracolumbar scoliosis. A chest radiograph (Fig. 1) showed a semicircular density in the right upper lobe, which cleared gradually with ther¬ apy. There was radiologic evidence of chronic sinusitis. Sputum culture grew Hemophilus influenzae and Pseudomonas at the age
Table I.Clinical features of three adults with cystic fibrosis
Case reports Patient 1
A 26-year-old electrician was seen in consultation because of dyspnea on exertion. Episodes of vomiting during the first 6 months of his life had responded to the elimination of milk and milk products from his diet. His childhood history was otherwise unremarkable and he had par-
142 CMA JOURNAL/JANUARY 24, 1976/VOL. 114
absent; + present; | increased; decreased; NI not investigated. *Normal range, 9 to 56 mmol//. =
i
=
=
=
=
aeruginosa. Pulmonary function
tests per¬
formed after clinical and radiologic re¬ covery showed moderately severe airway obstruction with a good response to bron¬ chodilator inhalation (Table II). A 72-hour stool collection, when his dietary intake of fat was 100 g daily, contained 45 g of fat (normal, < 15 g) and 8.2 g of total fecal nitrogen (normal, < 3 g). A secretin stimulation test showed a decreased volume of pancreatic secretion and decreased bicarbonate concentration in the secretions. A rectal biopsy showed normal rectal mucosa and a skin biopsy from the forearm showed morphologically normal sweat glands. A semen sample could not be obtained for analysis. His symptoms resolved on treatment
Table II.Results of function tests
pulmonary Patient no.
Test Vital capacity, % of predicted Residual volume (RV), % of predicted 122 Total lung capacity (TLC), %of predicted 97
1 102
98
82
111
125
100
93
RV/TLC, % observed/ % predicted 34/27 26/25 35/30 FEVi*/FVCt,%observed/% 69/80 77/85 70/84 predicted 152 113 125 DlCOJ, % of predicted *FEVi forced expiratory volume in 1 second. fFVC forced vital capacity. jDlCO single-breath carbon monoxide diffusing capacity (ml/min- mm Hg). =
=
=
FIG. 1.Patient 1:
density abutting
on
FIG. 2.Patient 1: after radiograph in
upper lobe minor fissure.
Right
with tetracycline, physical therapy and pancreatic replacement therapy. Contrary to instructions he discontinued postural drainage after discharge and was readmitted 3 months later with right middle lobe atelectasis and pneumonia (Fig. 2), which responded very slowly to therapy. Sputum culture on this occasion grew P. aeruginosa and Staphylococcus aureus. No spermatozoa could be seen in a sample of ejaculate less than 0.1 ml in volume.
Patient 2
19-year-old junior college student was in consultation because of a produc¬ tive cough. At the age of 5 he had undergone tonsillectomy and adenoidectomy, and cobalt irradiation for multiple episodes of pu¬ A
seen
rulent otitis media which resolved there¬ after. Between the ages of 5 and 16 he was well, apart from frequent episodes of vague dyspepsia following meals. From the age of 16 he had had a cough productive of increasing amounts of foul green sputum. He had severe night sweats, an almost continuous postnasal drip and frequent upper respiratory tract infections. He had no wheezing or dysp¬ nea and played many sports competitively at college. One month before the consulta¬ tion a sputum culture had grown many colonies of coagulase-positive S. aureus. Bronchograms performed at that time were reported as showing "bilateral upper lobe cylindrical bronchiectasis of moderate degree and changes in the remainder of the bronchi consistent with chronic bron¬ chitis"; resective lung surgery was dis¬ cussed. He also complained of vague ab¬ dominal cramps following meals. His paternal great-grandmother had died of "asthma" at the age of 40 and his paternal grandmother had suffered from asthma, sinusitis, a productive cough and abdominal complaints all her life. His 65year-old nonsmoking maternal grandfather had "chronic bronchitis". His 4-year-old sister had recurrent upper respiratory tract infections. He was well developed and had no ab¬ normal physical findings. A chest radiograph showed patchy infiltrative disease in the right upper lobe (Fig. 3). Radiographs of the paranasal sinuses showed acute and chronic sinusitis. Pulmonary function testing showed mild
Collapse of right middle lobe with consolidation 3 months Fig. 1 was made.
airway obstruction (Table II) and some maldistribution of ventilation. Sweat elec¬ trolyte estimation showed a sodium value of 119 mmol// and a chloride value of 116 mmol//. A fecal smear was strongly positive for fat (Sudan III stain; and a duodenal aspi¬ rate was negative for trypsin. The patient could not produce a sample of semen for
analysis. Antral washings relieved his postnasal drip and he reported disappearance of his abdominal discomfort with pancreatic en¬ zyme replacement therapy (Pancrelipase, Cotazym). He was instructed in hydration and postural drainage and started on a suitable antibiotic regimen. His 4-year-old sister had sweat sodium
and chloride values of 124 mmol//. His 2-month-old brother had a sweat sodium value of 53 mmol// and a sweat chloride value of 40 mmol//, and repeat testing showed similar values. Other members of his family had values for sweat electrolytes well below the upper limits of normal. Patient 3 As a child this 20-year-old anthropology student had had recurrent rhinorrhea dur¬ ing the ragweed season. When he was 13 a
chronic cough, diagnosed
as
"sinusitis",
had developed. Between the ages of 15 and 20 he had had an average of six respira¬ tory tract infections per year, consisting of a cough productive of purulent sputum, wheezing, dyspnea on exertion, chills and fever. These episodes responded rapidly to antibiotics but tended to recur when anti¬ biotics were stopped. Sputum cultures at various times grew Klebsiella pneumoniae and S. aureus. Finger clubbing was first noted at the age of 18. He had no symp¬ toms tem.
referable to the gastrointestinal sys¬
His maternal grandmother had had a chronic productive cough all her life and had died at the age of 55 with a diagnosis of tuberculosis. He was well developed and had club¬ bing of the fingers and toes but no other important physical abnormalities. A chest radiograph showed a diffuse interstitial process in both lungs, most pronounced in the upper lobes. Magnifica¬ tion views showed endobronchial thicken¬ ing throughout both lung fields. Radio¬ graphs of the sinuses showed acute and
FIG. 3.Patient 2: right upper lobe.
Patchy infiltration in
CMA JOURNAL/JANUARY 24, 1976/VOL. 114 143
chronic sinusitis.
Sputum culture grew aureus and a mod¬ erate number of colonies of P. aeruginosa. Pulmonary function testing showed evid¬ ence of hyperinflation and airway obstruc¬ tion (Table II). Estimation of sweat electrolytes showed a sodium value of 118 numerous
colonies of S.
mmol// and a chloride value of 112 mmol//. Fat content of a 72-hour stool collection was slightly high, at 18.8 g, but trypsin was present in stool to a dilution of 1:80. Despite repeated courses of antibiotics sputum cultures continued to grow S. aureus and P. aeruginosa. Eight days after discharge he was readmitted with acute pancreatitis, which rapidly responded to conventional ther¬ apy. His sputum culture again grew P. aeruginosa and S. aureus. This patient failed to keep outpatient appointments and was lost to follow-up. However, correspondence from other hos¬ pitals indicated that his respiratory prob¬ lems were continuing.
Discussion The prognosis for patients with cystic fibrosis was greatly improved by the introduction of antibiotics:14 now more and more such patients survive into adult life.2,15 Adult patients with cystic fibrosis appear to fail into one of two
categories:
1. Those with moderate or severe respiratory disease who have had symp¬
toms typical of cystic fibrosis since in¬ fancy or childhood. For most of these patients the diagnosis is made in early life and they are often cared for by their pediatrician even into adult life, the internist seeing them only in con¬
sultation. 2. Those with mild
or
moderate
gastrointestinal disease whose symptoms in childhood were so mild that diagnosis was not made till later in life unless there was a family history of the disease, or who had no symptoms. These patients are encount¬ ered by the family physician or internist and present a challenge to practitioners pulmonary
or
of internal medicine.16 The patients described here fail into the second category and are remark¬ able for the lack of respiratory symp¬ toms in their early life. The absence of finger clubbing in two of these patients, in contrast to its presence in adult pa¬ tients, is consistent with the late onset of respiratory disease.7,8 The early med¬ ical history of these patients included ear infections, manifestations of allergy and vague abdominal complaints, none of which were sufficiently severe to cause anxiety to the patient or his parents. Recurrent otitis media (pa¬ tient 2) is a complication of cystic fi¬ brosis, and hearing loss and speechlanguage deficiency have been reported in children with cystic fibrosis and re¬
current otitis media.17 Nevertheless, otitis media is such a common disorder of childhood and responded so well to therapy in patient 2 that its relation to cystic fibrosis was understandably not considered at the time. Vague epi¬ sodes of abdominal pain are frequent in patients with cystic fibrosis and have been ascribed to transient fecal impaction or pancreatitis.12'18 Patient 2 gave
a history of mild dyspepsia from about the age of 6. These symptoms devel¬ oped in patient 1 much later in life. Results of pulmonary function tests in these patients were fairly typical of those for mild to moderate involvement of the lung by the disease.19 In these three cases the diagnosis was first suggested by the development of respiratory symptoms in a patient with a family history of respiratory disease. The diagnosis was confirmed by the finding of elevated sweat electrolyte values. Pulmonary infections due to S. aureus or P. aeruginosa, or both, oc¬ curred at some time in each of these patients and is characteristic of cystic fibrosis. Pancreatic function was insuf¬ ficient in the two patients in whom it was investigated; however, this abnor¬ mality is not necessary for the diag¬ nosis2 and in children it frequently improves as they get older. Therefore, the combination of a suggestive family history in a patient with respiratory symptoms, especially when he is sus¬ ceptible to infection with S. aureus or P. aeruginosa or both, should prompt the physician to investigate the concen¬ tration of sodium and chloride in the patient's sweat. Sweat tests should be performed more than once because false-negative results are found.20 While there is some disagreement concerning the normal concentrations of sweat electrolytes in adults,21 the values in these three patients would be accepted by most workers as indicative of cystic fibrosis in the adult. The question of the importance of early diagnosis of cystic fibrosis in chil¬ dren has recently been debated, because methods of screening the population for cystic fibrosis will probably be available in the near future. There is good evidence that mortality and mor¬ bidity in children are reduced and sur¬ vival is prolonged by early and inten¬ sive therapy in a centre specializing in treatment of cystic fibrosis.14,15 How¬ ever, it is less clear whether diagnosis when the child is still asymptomatic alters the prognosis.22'24 All of these studies refer to patients in whom the diagnosis was made early in life and not to adults. Distinguishing the adult patient with
a predominantly genetic disease, cystic fibrosis, from the patient with respira¬
tory disease due mainly
144 CMA JOURNAL/JANUARY 24, 1976/VOL. 114
to environ¬
mental
causes
is
lowing reasons:
important for the fol¬
Failure to realize that a patient cystic fibrosis may result in respira¬ tory infections being treated with inappropriate antibiotics. Respiratory in¬ fections in such patients are frequently .
has
caused by S. aureus and P. aeruginosa, and the latter is found more frequently after inappropriate antibiotic therapy. Moreover, in severely ill patients there is a high incidence of infection by atypical "mucoid" strains of P. aerugi¬ nosa, which appear to be much more invasive and less sensitive to antibiotics than the more typical "rough" organ¬ isms.25 Serum from a patient with cystic fibrosis may contain a factor that in¬ hibits preferentially the phagocytosis of P. aeruginosa by alveolar macro¬
phages.26
. Consideration of resective lung surgery may be considerably modified when the progressive nature of the dis¬ order is recognized. Such surgery had been discussed for patient 2 because of bronchiectasis before referral. Also, the demonstration of "meconium ileus equivalent" in adult patients with cystic fibrosis18'27 should prompt surgeons to try conservative therapy before performing laparotomy when these pa¬ tients have an intestinal obstruction.28'29 . The complications of cystic fibro¬ sis differ in many respects from those of other respiratory diseases. Diabetes mellitus is more frequent in patients with cystic fibrosis than in those with other chronic respiratory diseases.30 Liver dysfunction in a patient with cys¬ tic fibrosis could well be due to the diffuse nature of the underlying disease rather than to a second pathologie pro¬
cess.18 Gastrointestinal complications and decreased fertility have been re¬ ported. Such complications can be anti¬ cipated and sometimes prevented if the nature of the problem is recognized
(Table III).
. It is important that the patient know his or her state of fertility. While reports have appeared of males with cystic fibrosis who appeared to be fertile,11 the majority of males with the disease are infertile.31 While females with the disease are less fertile, they are often capable of childbearing. How¬ ever, they have a much higher incid¬ ence of obstetric complications. The pregnancy itself may initiate rapid decompensation in their cardiopulmonary status and may, in fact, contribute to death in the early postpartum period.32 Since the severity of such complications is related to the degree of pulmonary disease, we would not expect a noticeable increase in the complications of pregnancy in this group of patients. However, because the woman with cys¬ tic fibrosis has a much greater chance
WW, CUGELL DW, ZELKOWITZ PS, et al: Cystic fibrosis of the pancreas; a comparison of the pulmonary manifestations in children and young adults. Chest 59: 306, 1971 TAussio LM, LosEcic CC, Di SANT'AGNE5E PA, et al: Fertility in males with cystic fibrosis. N Engi I Med 287: 586, 1972 GRACEY M, ANDERSON CM: Cystic fibrosis of the pancreas in adolescence and adulthood. Australas Ann Med 18: 91, 1969 GiBsoN LE, COOKE RE: A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilising pilocarpine by iontophoresis. Pediatrics 23: 545, 1959 MEARNS MB: Treatment and prevention of pulmonary complications of cystic fibrosis in early childhood. Arch Dis Child 47: 5, 1972 SHWACHMAN H, REDMOND A, KNAW KT: Studies in cystic fibrosis. Report of 130 patients diagnosed under 3 months of age over a 20 year period. Pediatrics 46: 335, 1970 POGUE RE, WARWICK WJ: Cystic fibrosis. A new challenge to internal medicine. Minn Med 52: 1551, 1969 FoRcucci RA, STARK EW: Hearing loss, speech-language and cystic fibrosis. Arch Otolaryngol 96: 361, 1972 KOPEL FB: Gastrointestinal manifestations of cystic fibrosis; a review. Gastroenterology 62: 483. 1972 RAms DV, MACKLEM PT, CHRIsTIE RV: Respiratory Function in Disease, second ed, Philadelphia, Saunders, 1971, p 240 WARWICK WJ: How cystic fibrosis can be confused with chronic bronchitis and bronchial asthma. Minn Med 52: 1476, 1969 SEKELJ P, BELMONTE M, RASMUSSEN K, et al: Survey of electrolytes of unstimulated sweat from the hand in normal and diseased adults. Am Rev Respir Dis 108: 603, 1973 LAWSON D: Cystic fibrosis: assessing the effects of treatment. Arch Dis Child 47: 1, 1972 WARWICK WJ, POGUE RE: Computer studies in cystic fibrosis, in Proceedings of the Sih International Cystic Fibrosis Conference, edited by LAWSON D, London, Cystic Fibrosis Trust, 1969, p 320 BRIMBLECOMBE FSW, CHAMBERLAIN J: Screening for cystic fibrosis. Lancet 2: 1428, 1973 DOGGErIT RG, HAlutisoN GM: Pseudomonas aeruginosa. Immune status jn patients with cystic fibrosis. Infect Immun 6: 628, 1972 BOXERBAUM B, KAGUMBA M, MArrHaWs LM: Selective inhibition of phagocytic activity of rabbit alveolar macrophages by cystic fibrosis serum. Am Rev Respir Dis 108: 777, 1973 IBAcH EG: Meconium ileus equivalent in an adult patient. Med I Aust 1: 268, 1968 NOBLETT HR: Treatment of uncomplicated meconium ileus by Gastrografin enema: a preliminary report. I Pediatr Surg 4: 190, 1969
Table Ill-Some complications of cystic fibrosis in adults Respiratory system Nasal polyposis, sinusitis T tendency for viral infections to lead to bacterial pneumonias Bronchiectasis, chronic bronchitis Atelectasis, pneumonia Pneumothorax, empyema
10. ADDINOTON
Gastrointestinal system Intermittent abdominal cramps and pains Meconium ileus equivalent Duodenal ulcer Volvulus and intussusception Pancreatitis Hepatic (biliary) cirrhosis, portal hypertension, hypersplenism, etc.
14.
Genitourinary system Sterility in males, .L fertility in females T morbidity and mortality in pregnancy I fetal mortality Other Heat stroke, Na. depletion, leading to shock if ill Diabetes mellitus Pulmonary hypertension and cor pulmonale Polycythemia, hemosiderosis
11.
12. 13.
15.
16. 17. 18. 19. 20. 21.
22.
of having a similarly affected child, advice on contraception should be offered to all women with cystic fibrosis irrespective of severity of their disease.33 0 Making the diagnosis will initiate appropriate screening of siblings and children and so allow early diagnosis of the disease in near relatives. The clinical spectrum of cystic fibrosis is insufficiently appreciated. As Warwick20 has commented, "If a patient has asthma or chronic bronchitis and has never had a sweat test, it would be sheer medical folly to perpetuate an incorrect diagnosis by failing to do a sweat test because the patient was in his late teens or twenties." I thank John F. Murray, MD and Warren Gold, MD for helpful comments during the preparation of this paper and for permission to discuss patient 3.
References 1. ANDERSON DH: Cystic fibrosis of the pancreas and its relation to celiac disease. Am J Dis Child 56: 344, 1938 2. SCHWACHMAN H, KULCZYCKI LL: Long term study of 105 patients with cystic fibrosis. Am J Dis Child 96: 6, 1958 3. CECE JD, HENRY JP, ToiGo A: Pancreatic cystic fibrosis in an adult. JAMA 181: 31, 1962 4. POLGAR G, DENTON R: Cystic fibrosis in adults; studies of pulmonary function and some physical properties of bronchial mucus. Am Rev Respir Dis 85: 319, 1962 5. ANDERSON EG, LA5ZLO G, BROWN HM: A case of mucoviscidosis in an adult. Br J Dis Chest 59: 173, 1965 6. COArss EO: Characteristics of cystic fibrosis in adults; a report of 7 patients. Dis Chest 49: 195. 1966 7. TOMASHEFSKI iF, CHRISToFoRIDIS AJ, ARDULLAK AK: Cystic fibrosis in young adults; an overlooked diagnosis with emphasis on pulmonary function and radiological patterns. Chest 57: 28. 1970 8. GRAND Ri, TALAMO RC, DI SANT'AGNESE PA, et al: Pregnancy in cystic fibrosis of the pancreas. JAMA 195: 993. 1966 9. JONES JS: Adult cystic fibrosis (mucoviscidosis). Br I Dis Chest 64: 25, 1970
23.
24.
25. 26. 27. 28.
29. LILLIEBRIDGE CB, DOCTOR JM, EIDELMAN 5: Prophylaxis of meconium ileus equivalent with N-acetyl cysteine. I Pediatr 71: 887,
1967 30. ROSAN RC, SHWACHMAN H, KULCZYCKI LL:
Diabetes mellitus and cystic fibrosis of the pancreas. Am I Dis Child 104: 625, 1962
31. KAPLAN E, SCHWACHMAN H, PERLMUTI-ITER AD,
et al: Reproductive failure in males with cystic fibrosis. N Engi I Med 279: 65, 1968 32. LARSEN JW: Cystic fibrosis and pregnancy. Obstet Gynecol 39: 880, 1972 33. ANDERSON VE: Genetic counselling for parents. Minn Med 52: 1570, 1969
DISSEMINATED HISTOPLASMOSJS Continued from page 141 16. FUDENBERG HH, LEvIN AS, SPITLER LE, et al: The therapeutic uses of transfer factor. Hosp Practice 95, 1974 17. WHrrcOMa ME, ROcIcs.iN RE: Transfer factor therapy in a patient with progressive primary tuberculosis. Ann Intern Med 79: 161, 1973 18. CATANZARO A, SPITLER L, MOSER. KM: Immunotherapy of coccidioidomycosis. I Clin
Invest 54: 690, 1974
19. KIRKPATRICK
CH,
WILSON
WEC,
TALMAGE
DW: Immunologic studies in human organ transplantation. IExp Med 119: 727, 1964
20. JENSEN K, PATNODE RA, TOWNSLEY HC, et al: Multiple passive transfer of the delayed type of hypersensitivity in humans. Am Rev
Resp Dis 85: 373, 1962
21. PAQIJE RE, KNISKERN P1, DRAY 5, et al:
Transfer of the cell-migration inhibition correlate of delayed hypersensitivity in humans with nondialyzable components of leucocyte lysates from humans sensitized to histoplasmin and coccidioidin. Cell Immunol 6: 368, 1973 22. THOR DE, DRAY 5: The cell-migration-inhibition correlate of delayed hypersensitivity. I Immunol 101: 469, 1968
Apresoline
the unique "ADD ON" antihypertensive INDICATIONS: Various forms of hypertension: fixed essential hypertension, whether of benign or malignant character; hypertension associated with acute and chronic glomerulonephrit is; nephrosclerosis; hypertensive toxemias of pregnancy, pre-eclampsia, and eclampsia. DOSAGE: Hypertension: Orally: In general after initiating therapy gradually increase dosage, adjusting according to individual response. As a single agent, initially 10mg, four times daily increasing slowly to a maximum practical dosage of 200mg daily. In combination with other hypotensive agents, lower dosages of APRESOLINE will be appropriate. Parenterally: When there is urgent need, therapy in the hospitalized patient may be initiated intravenously or intramuscularly. Usual dose is 20 to 40 mg, repeated as necessary. Certain patients, especially those with marked renal damage, may require a lower dose. Pressure may begin to fall within a few minutes after injection, with an average maximal decrease occurring in 10 to 80 minutes. Most patients can be transferred to oral APRESOLINE within 24 to 48 hours. Toxemia of Pregnancy: a) Early toxemia and hypertension of pregnancy: One 10-mg tablet orally 4 times daily, slowly increasing the dosage up to 400 mg per day, or until a therapeutic result is obtained. b) Late toxemia and pre-eclampsia: Give 20 to 40 mg intramuscularly, or slowly by direct intravenous injection or infusion. Repeat as necessary. SIDE EFFECTS: Tachycardia, headache, palpitation, dizziness, weakness, nausea, vomiting, postural hypoterision, numbness and tingling of the extremities, flushing, nasal congestion, lachrymation, conjunctival injection, dyspnea, anginal symptoms, rash, drug fever, reduction in hemoglobin and red cell count, giant urticaria, and a lupus-like syndrome (arthralgia) in some cases following administration for long periods. CAUTIONS: Use cautiously in the presence of advanced renal damage and recent coronary or cerebral ischemia. APRESOLINE may potentiate the narcotic effects of barbiturates and alcohol. Peripheral neuritis evidenced by paresthesias, numbness and tingling has been observed. Published evidence suggests an anti-pyridoxine effect and addition of pyridoxine to the regimen if symptoms develop. OVERDOSAGE: Symptoms: Hypotension and tachycardia. Treatment: Gastric lavage or, in the absence of coma, emetics. In the presence of hypotension, cautiously give norepinephrine (intravenously) or ephedrine to raise the blood pressure without increasing tachycardia. Avoid epinephrine. General supportive measures include intravenous fluids, external heat and elevation of foot of bed. SUPPLIED: All forms contain hydralazine hydrochlorideTablets of 10mg (yellow, scored); bottles of lOOTablets of 25mg (blue, coated); bottles of 100 and 500 Tablets of 50mg (pink, coated); bottles of 100 and 500. Ampoules of 1 ml aqueous solution containing 20 mg; boxes of 10.
CIBA DORVAL, QUEBEC
C-5003
CMA JOURNAL/JANUARY 24, 1976/VOL. 114 145
