Severe Respiratory Disease in Infants With Cystic Fibrosis

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Severe

Respiratory

Disease

in Infants

With Cystic Fibrosis

John D. Lloyd-Still, MB., M.R.C.P., Kon-Taik Khaw, M.D., and

Harry Shwachman, M.D.

From the Division of Clinical Nutrition, Department of Medicine, The Children’s Hospital

Medical Center, and the Department of Pediatrics, Harvard Medical School, Boston

ABSTRACT. The diagnosis, management and prognosis of

17 infants with cystic fibrosis (CF) and severe respiratory

disease were reviewed for the period 1968 to 1972. The

clinical course of these infants was characterized by a

bronchiolitis-like syndrome with failure to thrive and

malnutrition. Arterial blood gases demonstrated marked hypoxemia (mean Pao,, 37.5 mm Hg ). Tracheal cultures

showed a predominance of gram-negative microorganisms

with Pseudomonas aeruginosa, Kiebsiella pneumonkie and

Escherichia coli predominating. Corticosteroids were used

in all patients. Despite vigorous therapy including

anti-biotics there was a 60% mortality. A delay in the diagnosis

of CF from the onset if respiratory symptoms with a mean

of six weeks was considered an important factor affecting

survival. This data supports the need for developing a

reli-able screening test for CF at birth. Pediatrics, 53:678, 1974,

CYSTIC FIBROSIS, RESPIRATORY FAILURE, BRONCHIOLITIS,

HY-POXEMIA, CORTICOSTEROIDS.

Concomitant with the improved survival of pa-tients with cystic fibrosis (CF)’ has been an in-crease in the variety and frequency of complica-tions. Recent publications have emphasized the specific problems of pneumothorax,2 massive he-moptysis,3 diabetes,4 sterility5 and psychological problems.#{176} In 1970, we reported on a 20-year ex-perience of 130 infants diagnosed under 3 months

of age. Using the life table technique a calculated

survival rate at age 20 for these patients was 77%.

We were impressed with the number that died in

infancy as a result of severe pulmonary

involve-ment. There were 29 deaths in this series from

which patients with meconium ileus were excluded. Moreover, despite advances in the surgical

treat-ment of meconium ileus7 a high mortality from

subsequent respiratory complications remains.

In 1953, di Sant’Agnese described the dangers

of lobar atelectasis in cystic fibrosis,8 with nine of

the 11 infants with atelectasis dying in the first

year of life. However, other infants with cystic fibrosis may develop respiratory distress without

evidence of lobar atelectasis. In these critically ill infants, despite the variable radiological findings,

hyperinflation is a constant feature. Their clinical

course is characterized by a bronchiolitis-like syn-drome with secondary chronic obstructive pulmo-nary disease. Marked respiratory distress, coughing,

wheezing, poor air exchange, increased AP

di-ameter of the chest, cyanosis and hypoxemia are noted. Fever is usually absent. Failure to thrive and malnutrition result from the feeding difficulties and the effects of pancreatic insufficiency. The pre-dominant respiratory complaints may not suggest

the diagnosis of CF and many such infants

suc-cumb without a definitive diagnosis or are

diag-nosed late in the course of the disease. This report

reviews the diagnosis, management and prognosis of such infants.

CLINICAL MATERIAL

This study includes 17 infants under 1 year of age admitted to the hospital because of respiratory distress in whom CF was diagnosed during their initial hospitalization, with the exception of three infants with meconium ileus who were diagnosed soon after birth. The number of newly diagnosed

patients with CF and those under 1 year seen in

this institution from 1968 to 1972 is shown in Table

(Received July 17; revision accepted for publication October 4, 1973.)

Supported in part by a grant from the National Cystic

Fibrosis Research Foundation and the Division of Arthritis

and Metabolic Disease, National Institutes of Health, Public

Health Service.

ADDRESS FOR REPRINTS: (H.S.) The Children’s

Hos-pital Medical Center, 300 Longwood Avenue, Boston,

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TABLE I

NEWLY DIAGNOSED PATIENTS WITa CYSTIC FIBROSIS AT

CHMC BOSTON FROM 1968-1972, WIrH SPECIAl.

REFERENCE TO INFANTS WITH SEVERE

RESPIRAIORY DISEAsL

1)iagnosed

lear lotal Ne’u (5nder 1

Patients Fear

Infants With Seicre

Respiratory

1)iseas-Total I)ied

I. In this five-year period 30% of all newly diag-nosed patients were under 1 year of age. Twenty-one percent of these infants had severe respiratory complications, and 60% of them died. The clinical, biochemical, and pathological findings are listed in Table II. There were 11 males and 6 females. Thirteen of the 17 infants were initially admitted to outside hospitals and then transferred. The mean birth weight was 2.9 kg (range of 1.9 to 3.5 kg). The mean age of onset of respiratory symptoms

was 1.8 months and of the diagnosis of CF was

3.2 months. The respiratory rate was persistently over 60 per minute and often over 80 per minute. Fever was unusual. The mean WBC was 15,600/cu

mm (range of 7,800 to 28,200/cu mm) . All patients

had absent trypsin in their stool. The mean serum protein was 5.5 gm/100 ml (range of 4.4 to 6.6 gm/ 100 ml). The mean gammaglobulin of seven patients was 0.46 gm/100 ml. Seven infants survived the acute illness and their average stay in the hospital was 44.3 days indicating the severity of their dis-ease. Ten of the infants died, including the three with meconium ileus.

ARTERIAL BLOOD GASES

These were estimated in 13 patients (Table II) and were characterized by severe hypoxemia

(

mean

Pao2, 37.5 mm Hg). The patients who died had

more severe hypoxemia

(

mean Pao2, 33 mm Hg)

and this was accompanied by hypercapnea (mean Paco2, 59.4 mm Hg) . The pH reflected the respira-tory acidosis which on occasion was aggravated by metabolic acidosis.

CHEST X-RAYS

Severe abnormalities were demonstrated on all

the chest roentgenograms. Hyperinflation was a

constant feature and this was the only abnormality in four infants at the onset of their illness. Right upper lobe atelectasis was seen in 11 out of the 17 infants. However, the left upper lobe (7/11 ), right

middle lobe

(

5/ 17

)

, lingula

(

4/ 17) , left lower lobe

(

4/ 17) , and right lower lobe

(

4/ 17) were also

affected. Many of these changes were transient. The heart was enlarged from cardiac failure in the ten infants who died.

BACTERIOLOGY

Tracheal aspirate culture showed a predomin-ance of gram-negative bacteria (Table II

)

with

Pseudomonas aeruginosa

(

11/17), Kiebsiella

pneu-moniae

(

11/17) and Escherichia coli (8/17)

pre-dominating. Staphylococcus aureus (5/17) was the major gram-positive microorganism isolated.

Can-dida albicans was present in five infants. The

dis-tribution of gram-negative microorganisms was

sim-ilar in those infants who died to those who

sur-vived. There was a good correlation between the microorganisms isolated on the tracheal culture and at autopsy from the lungs. Staphylococcus au-reus was isolated from the tracheal aspirate of four of the seven infants who survived, but in only one of the ten infants who died. Staphylococcus aureus

was not isolated at autopsy from blood or lung

culture.

ANTIBIOTICS

A combination of antibiotics was given parenter-ally to each patient. Oxacilhin, 200 mg/kg/day, was given to all 17 infants. Other antibiotics were gentamicin, 3 to 5 mg/kg/day (9/17) ; colistimeth-ate, 3 to 5 mg/kg/day (7/17) ; and kanamycin, 15 mg/kg/day (6/17) . Chioramphenicol, 50 mg/

kg/day (7/17), was given orally. There was no difference in the antibiotic regimen given to the group that survived compared to the infants that died.

CORTICOSTEROIDS

Corticosteroids were ultimately administered to all 17 infants. Hydrocortisone Sodium Succinate,

10 mg/kg/24 hr intravenously, or prednisone, 1 to 2 mg/kg/24 hr orally, was administered. In five pa-tients this therapy was only given terminally. The drug was usually tapered following discharge from the hospital. The average duration of therapy in the patients who survived was 102 days. The pro-longed duration of corticosteroids required in some infants was necessitated by the tendency to relapse

when the dosage was discontinued. Four of the

seven infants who survived have subsequently wheezed with further respiratory tract infections.

OTHER THERAPY

Ultrasonic mist ten therapy and oxygen were al-ways administered. Postural drainage, positioning, clapping and vibrating were carried out from three to six times a day depending on the physical

con-1968 59 19 5 2

1969 63 17 2 2

1970 50 1 3 1) 3

1971 55 16 2 2

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dition of the patient. Aminophylline, 12 to 16 mg/ kg/24 hr, was given intravenously to all infants and iodides to some. Digitalis and diuretics were ad-ministered to all the infants with cardiac failure. Six desperately ill infants required mechanical yen-tilation with a respirator but only one survived.

AUTOPSY FINDINGS

The lungs of all infants showed widespread

bronchopneumonia and bronchiectasis. Infarction

and hemorrhagic pneumonia were seen in the two

infants who died with E. coli and P. aeruginosa

bacteremia. All the infants had evidence of pan-creatic fibrosis. Hepatic changes included cirrhosis, congestion, and fatty metamorphosis. Areas of

ad-renal hemorrhage were noted in four out of the

nine autopsies, but were severe in only one

in-stance.

PRESENT STATUS

The present clinical rating9 of the seven surviving infants is shown in Table II. The majority of the patients are in the so-called mild category (56-70).

This system of clinical evaluation documents the severity of the disease and is of prognostic signifi-cance. Four categories are assessed including gener-al activity, physical findings, nutritional status and the appearance of the chest roentgenogram. Each category is scored out of a total of 25 points, with 100 points representing a perfect score.

DISCUSSION

The high mortality of infants with CF, both with meconium ileus1#{176}and without,1’ has been well

recognized in the past. The data from Table II

show that the first 6 months of life still account for a significant mortality, and reinforce the need for reliable screening techniques for the detection of infants with CF at birth or shortly thereafter. We believe that the high mortality in infants with CF and severe respiratory distress may be related to delay in diagnosis and can be reduced with the institution of an appropriate therapeutic program including antibiotics. In our patients there was an average delay of six weeks from the onset of res-piratory symptoms to diagnosis and proper therapy. Only one of the 17 patients had a family history of CF.

The differential diagnosis is mainly from bron-chiolitis, asthma and heart disease. Bronchiolitis usually affects infants under 6 months and, when it occurs in epidemics, up to 80% of cases may be caused by the respiratory syncytial virus.12 How-ever, it may occur sporadically in nonepidemic pro-portions, at which time a variety of other viruses may be isolated.13 The clinical findings in bron-chiolitis may be indistinguishable from those in

infants with CF. The initial pulmonary lesion in our infants with CF could be a viral bronchiolitis complicated by secondary bacterial infection. Viral cultures were not performed. The infectious and allergic aspects of bronchiolitis are confusing,14 but

Rooney and Williams’5 reported that 56% of

in-fants with proven viral bronchiolitis developed sub-sequent wheezing. It is interesting that four of our

seven survivors have also developed subsequent

wheezing. Congenital heart disease must be

ex-cluded and some infants have undergone cardiac

catheterization before CF was recognized.

Myo-cardial fibrosis has been reported in infants with CF16 but was not present in these infants.

Arterial blood gas estimations were done in 13 infants. The Pao2 values in Table II confirmed the

severe hypoxia that is characteristic of these in-fants and correlated well with the increased respira-tory rate (60 to 80 per minute). Reynolds17 has

shown the physiological correlations between Pao

and Paco2 with the respiratory rate. Intermittent positive pressure breathing was not used unless the raised Paco2 was causing symptoms.

The principles of antibiotic therapy in CF are discussed elsewhere.’8’19 Our present preference in these ill infants is for parenteral oxacillin and

gentamicin being dependent on tracheal

iso-lates and sensitivity. The absence of S. aureus

from autopsy cultures of the lungs in our infants is noteworthy. It is quite possible that our anti-biotic therapy effectively eliminated the

Staphy-lococcus and left the resistant gram-negative micro-organisms to flourish. The predominance of gram-negative microorganisms from the tracheal aspirate cultures supports this hypothesis.

Corticosteroids do not seem to be of any signifi-cant benefit in bronchiolitis,2#{176} but a controlled trial of their use in pertussis demonstrated a significant

beneficial effect, especially in infants below 6

months of age.2’ There are no controlled trials of their use in infants with severe respiratory distress and CF, although other investigators have noted

clinical improvement? Corticosteroids may

de-crease the edema and cellular infiltration in the bronchioles, and they were given to all the patients in this series. Corticosteroids were not used until several days of conventional therapy ( including

in-travenous aminophylline) had elapsed. Some of the indications for their use include a lack of

(5)

Withdrawal of corticosteroids may result in a relapse

and Table II shows the prolonged duration of

therapy required.

Improvement of the nutritional status is impera-tive as delay in diagnosis leads to severe malnutri-tion and hypoproteinemia. The paroxysmal cough-ing may cause vomiting, feeding problems, and aspiration pneumonia. Despite the tachypnea, these infants are usually hungry and difficult to satisfy in spite of caloric intakes of 150 to 200 calories/kg! day. We now prefer frequent small feeds of a for-mula containing glucose, medium-chain triglycer-ides and a casein hydrolysate

(

Pregestimil).

The prognosis of infants with severe respiratory distress and CF is still poor. Moreover, the clinical scores of the surviving patients in this series vary from 50 to 82, thus demonstrating that even re-covery from severe respiratory disease in infancy implies a poorer prognosis for the patient with CF.

REFERENCES

1. Shwachman, H., Redmond, A., and Khaw, K. T.:

Studies in cystic fibrosis: Report of 130 patients

diagnosed under 3 months of age over a 20-year period. Pediatrics, 46:335, 1970.

2. Shwachman, H., and Holsclaw, D.S. : Pulmonary

corn-plications of cystic fibrosis. Mimi. Med., 52:1521,

1969.

3. Holsclaw, D.S., Grand, R.J., and Shwachnian, H.:

Mas-sive hernoptysis in cystic fibrosis. J. Pediat., 76:829, 1970.

4. Handwerger, S., Roth, J., Dorden, P., di Sant’Agnese, P., Carpenter, D. F., and Peter, C.: Glucose

intol-erance in cystic fibrosis. New Eng. J. Med.,

281:-451, 1969.

5. Kaplan, E., Shwachrnan, H., Perlmutter, A.D., Rule, A.,

Khaw, K. T., and Holsclaw, D. S.: Reproductive

failure in males with cystic fibrosis. New Eng. J.

Med., 279:69, 1968.

6. McCollurn, A. T., and Gibson, L. E.: Family adaptation

to the child with cystic fibrosis. J. Pediat., 77:571,

1970.

7. Noblett, H. R.: Treatment of uncomplicated meconiurn

ileus by gastrografin enema: A preliminary report.

J. Pecliat. Surg., 4:190, 1969.

8. di Sant’Agnese, P. : Bronchial obstruction with lobar

atelectasis and emphysema in cystic fibrosis of the

pancreas. Pediatrics, 12: 178, 1953.

9. Shwachman, H., and Kulczycki, L. L.: Long-term study

of 105 patients with cystic fibrosis. Amer. J. Dis.

Child., 96:6, 1958.

10. Donnison, A. B., Shwachrnan, H., and Gross, R. E. : A

review of 164 children with meconiurn ileus seen

at the Children’s Hospital Medical Center, Boston.

Pediatrics, 37:833, 1966.

11. Shwachman, H., Leubner, H., and Catzel, P.:

Muco-viscidosis. Advances Pediat., 7:249, 1955.

12. Denny, F. W.: The replete pediatrician and the etiology

of lower respiratory tract infections. Pediat. Res.,

3: :463, 1969.

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Chan-ock, R. M. : Serious respiratory tract illness as a

result of Asian Influenza and Influenza B infections

in children. J. Pediat., 61:205, 1962.

14. Simon, G., and Jordan, W. S., Jr.: Infectious and

aller-gic aspects of bronchiolitis. J. Pediat., 70:533,

1967.

15. Rooney, J. C., and Williams, H. E.: The relationship

be-tween proved viral bronchiolitis and subsequent

wheezing. J. Pediat., 79:744, 1971.

16. McGiven, E. R.: Myocardial fibrosis in fibrocystic

dis-ease of the pancreas. Arch. Dis. Child., 37:656,

1962.

17. Reynolds, E. 0. R.: Arterial blood gas tensions in acute

disease of lower respiratory tract in infancy. Brit.

Med. J., i:1192, 1963.

18. Huang, N. : In Guide to Drug Therapy in Patients With

Cystic Fibrosis. Atlanta: National Cystic Fibrosis Research Foundation, 1973.

19. Shwachman, H. In Kendig, E. L., Jr. (ed.) : Disorders

of the Respiratory Tract in Children: Cystic

Fibro-sis, Vol. I. Philadelphia: W. B. Saunders Company,

1972, p. 524.

20. Dabbous, I. A., Tkachyk, J. S., and Stamm, S. J. : A double blind study on the effects of corticosteroids

in the treatment of bronchiolitis. Pediatrics, 37:

477, 1966.

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Matsaniotis, N. : Steroids in treatment of pertussis: A controlled clinical trial. Arch. Dis. Child., 48:51,

1973.

22. Matthews, L. W., Doershuk, C. F., and Patterson, P. R.:

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1974;53;678

Pediatrics

John D. Lloyd-Still, Kon-Taik Khaw and Harry Shwachman