Pulmonary Function Abnormalities in Thalassemia Patients on a Hypertransfusion Program

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Pulmonary

Function

Abnormalities

in

Thalassemia

Patients

on a Hypertransfusion

Program

Thomas G. Keens, MD, Margaret H. O’NeaI, MD, Jorge A. Ortega,

MD, Carol B. Hyman, MD, and Arnold C.G.

Platzker,

MD

From the Neonatal-Respiratory Diseases Division and Hematology-Oncology Division, Childens Hospital of Los Angeles, and Department of Pediatrics, University of Southern California School of Medicine, Los Angeles

ABSTRACT. Pulmonary function tests were performed in 12 thalassemia patients on a hypertransfusion program

(age 18.4 ± 2.6 SEM years) to determine the presence of any abnormalities of lung function. These included spi-rometry, expiratory flow rates, body plethysmography, single-breath nitrogen washout, single breath carbon

monoxide diffusing capacity, and arterial blood gases.

Only one patient had normal pulmonary function.

Arte-na! hypoxemia was present in ten of 12 patients at rest.

The total lung capacity (TLC) was normal. The residual

volume was abnormally increased in five of 12 patients.

The slope of phase III of single breath nitrogen washout

curve was abnormal in five of 12 patients, but the closing

volume was normal. The maximal expiratory flow rate at

60% total lung capacity was decreased in four of 12

patients, suggesting the presence of small airway disease.

The single breath carbon monoxide diffusing capacity

was normal in all patients. These pulmonary function

abnormalities did not correlate with age or the cumulative

amount of iron via blood transfused. The small airway

obstruction, hyperinflation; and hypoxemia observed in

thalassemia patients on a hypertransfusion program may

result from the basic disease, iron deposition in the lungs,

or other factors. Pediatrics 65:1013-1017, 1980;

thalas-semia, hypertransfusion program, small airway obstruc-tion, pulmonary function abnormalities, hypoxemia.

Thalassemia major is a disorder of hemoglobin

synthesis.’3 The clinical manifestations are

second-ary to decreased oxygen delivery to the tissues,

ineffective erythropoiesis, and iron overload.2’3 To

correct this, thalassemia patients are often treated

according to a hypertransfusion program, which

maintains the hemoglobin concentration at or

Received for publication April 24, 1979; accepted Aug 7, 1979. Reprint requests to (T.G.K.) Neonatal-Respiratory Diseases Di-vision, Childrens Hospital of Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027.

above 10.5 gm/100 rnl. Although this has

im-proved the oxygen carrying capacity of the blood

with some alleviation of the cardiomegaly and bony

malformations,5’6’8’9 thalassemia patients on a

hy-pertransfusion program have a reduced exercise

tolerance,4’7 suggesting that tissue hypoxia may not

be eliminated. Furthermore, increased red cell

pro-duction may persist on hypertransfusion

therapy,4’6”#{176} possibly responding to a hypoxic drive.

Although cardiac dysfunction is a major cause of

death in patients with thalassemia major,”2

pul-monary involvement has not been described. Iron

deposition has been observed on postmortem

ex-amination of the lungs from patients receiving

mu!-iple blood transfusions.’3 Iron deposition may also

occur in the lungs of thalassemia patients on

hy-pertransfusion programs, and this may cause

pu!-monary function abnormalities.

MATERIALS AND METHODS

Pulmonary function tests were performed on 12

patients with thalassemia major on a

hypertrans-fusion program at Childrens Hospital of Los

Ange-les. Their hemoglobin concentrations have

contin-uously been maintained at 10.5 gm/100 ml or

greater since the beginning of the hypertransfusion

program in 1969, or for an average of 6.8 ± 0.6

(SEM) years. The 12 thalassemia patients ranged

in age from 6.3 to 30 years (mean 18.2 ± 2.6 [SEM]

years). All but one of the patients were clinically

stable at the time of the study. No patient had

repeated pulmonary infection, and only patient 10

had symptoms that could be attributed to lung

disease. No patients were cigarette smokers, and

there was no family history of lung disease. All

patients were at least 6 years of age and were able

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The vital capacity and its subdivisions were mea- mean arterial oxygen tension (Pao2) was 79.1 ± 2.6

sured from a slow exhalation with a wedge spirom- mm Hg (P < .001). The mean carbon dioxide

ten-eter (Med Science model 270). Functional residual sion and pH were 41.6 ± 1.6 mm Hg and 7.40 ± 0.01,

capacity was measured with a variable pressure respectively. The single breath diffusing capacity of

body plethysmograph by the methd of Dubois et the lung for carbon monoxide was normal in all

al.’4 patients.

Forced vital capacity, forced expiratory volume The TLC was normal in all patients. The vital

in one second, midmaximal expiratory flow rate, capacity was normal in most. The residual volume

peak expiratory flow rate, and the maximal expira- (RV) was abnormal in five of 12 patients (47%).

tory flow-volume curve were obtained from forced This is shown in Fig 2. The mean RV/TLC was 30.6

exhalations into a wedge spirometer (Med Science ± 2.3% (P < .025), indicating the presence of

hyper-model 270). The maximal expiratory flows at 80% inflation.

total lung capacity (TLC) (1 80%), 70% TLC The midmaximal expiratory flow rate was normal

(Vmax

70%), and 60% TLC 60%) were standard- in all patients, and the forced expiratory volume in

ized for different lung volumes by dividing the ob- one second abnormal in only one. On the maximal

served flow rates by TLC.’5”6 The results were

expressed as TLC/sec. Airways resistance was

mea-sured by the method of Dubois et a!’7 with a

van-able pressure body plethysmograph. Specific airway

conductance was obtained from the simultaneously

determined airways resistance and thoracic gas

vo!-I

too

90

ume.

. . . .

The single breath diffusing capacity of the lung

for carbon monoxide was determined by the method

P002 80

(mmKg)

70

#{149}

:

#{149}

of Ogilvie et al.’8 The closing volume and slope of

phase III were obtained from a single breath nitro- 60

gen washout curve after a vital capacity inhalation

of 100% oxygen.’9 Arterial blood gases were

mea-sured on a blood sample from the radial artery in

seated patients breathing room air at rest.

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0

Any result was considered abnormal if it was AGE (YRS)

more than two standard deviations from the

regres-sion line of normal subjects obtained in this

labo-ratory and from the literature.’6’#{176} Group means

were compared by using the t test of the difference

between two means. Correlations between any two

parameters were made with a simple linear regres- 60

sion analysis.

50

RESULTS

The mean hemoglobin concentration of the thal- RV/TLC 40

#{149}

assemia patients at the time of study was 11.9 ± 0.5

(SEM) gm/100 ml. The mean cumulative blood

transfused was 81 ± 17 liters per patient, with an

average iron concentration of 1 gm per liter of

#{176}

20

1

packed cells. There was a significant correlation

between cumulative iron received via blood trans- Io

fusion and age by simple linear regression (r = .746;

P < .01). Patients 10 and 11 died with arrhythmia

and heart failure within a year of study. Patient 6

had clinical evidence of myocardial hemosiderosis,

but was well controlled on digitalis. No other

pa-tient had clinical heart or lung disease at the time

of stud

y.. .

Antenal hypoxemia was present m ten of 12

pa-tients (83%) at rest. This is shown in Fig 1. The

x

20 30

AGE (YRS)

Fig 2. Ratio of residual volume to total lung capacity

(RV/TLC) in percent is shown for the 12 thalassemia

patients vs age (in years). Individual data points are

shown. Hatched area represents mean ± 2 SD for normal

subjects.

0 I0 20 30

Fig 1. Arterial oxygen tension (Pao2) at rest (in mm

Hg) is shown for the 12 thalassemia patients vs age (in

years). Individual data points are shown. Hatched ar#{128}

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Thalassemia

EJ

Normal

I.5

FLOW

(TLC/sec)

0.5

0

Vmox \lmax

80% 70%

(ns.) (p<O.O5)

‘;‘max

60%

(p(O.O05)

Fig 3. Maximal expiratory flow rates at 80% total lung

capacity (TLC) (Vmax 80%), 70% TLC (Vmax 70%), 8.fld 60%

TLC (Vmax 60%) are shown in TLC/sec. Bars represent group means ± 1 SEM. Hatched bars represent

thalas-semia patients and clear bars normal subjects.

Pa 02

RV/TLC

SLOPE OF PHASE 1ff

Vmax 60%

Vmax 70%

Vmax 80%

FEV1/VC

MMEF

Fig 4. Percent of thalassemia patients with abnormal tests is shown for eight pulmonary function parameters.

expiratory flow-volume curve, flow rates became

more abnormal at lower percentages of TLC. This

is shown in Fig 3. Vmax 80% was abnormal in two of

12 patients (17%) with a mean of 1.20 ± 0.10 TLC/

sec (not significant). max (70%) was abnormal in

three of 12 patients (25%) with a mean of 0.91 ±

0.09 TLC/sec (P <.05). 60% was abnormal in

four of 12 patients (33%) with a mean of 0.56 ± 0.09

TLC/sec (P < .005). There was a significant

de-crease in flow rates compared to normal at lower

lung volumes by regression analysis of variance,

suggesting small airway obstruction (P < .0005).

The slope of phase III of the single breath

nitro-gen washout curve was abnormal in five of 12

pa-tients (42%). The mean value was 1.94 ± 0.21% N2/

liter (P < .005). Closing volume was normal in all

but one patient.

No pulmonary function parameter correlated

with age or cumulative iron via blood transfused.

The Pao2 was the most sensitive test for detection

of pulmonary function abnormalities, as shown in

Fig 4. Individual pulmonary function results are

given in the Table. As can be seen, only patient 3

had completely normal pulmonary function.

DISCUSSION

Although myocardial iron deposition is known to

cause cardiac dysfunction in thalassemia patients

on hypertransfusion programs,7”2 lung

involve-ment has not been described previously. However,

only one patient in this study had normal

puinto-nary function. Although cardiac failure can cause

pulmonary function abnormalities, it is unlikely

that the results of this study are due to cardiac

dysfunction alone. Only three patients had clinical

evidence of heart disease. Measurement of gas

ex-change parameters during exercise can differentiate

pulmonary from cardiac abnormalities,2’ but these

tests were not performed in this study.

___________________ Although hepatomegaly was present in most of

the older patients, this has not been associated with

small airway obstruction. One might expect

hepa-tomegaly to cause restrictive disease, but this was

_________

not observed in our patients. The observed

hypox-emia reflects pulmonary gas exchange

abnormali-ties. Although 2,3-diphosphoglycerate levels may

be altered in thalassemia,’#{176} these do not affect lung

function and were not measured in this study.

The results of this study suggest that thalassemia

patients on a hypertransfusion program develop

I I I I functional abnormalities consistent with small

air-0 25 50 75 00 way obstfliction. Hypoxia is the most striking

abnormality. This is known to be one of the most

sensitive indices of small airway disease in pediatric

patients.’6’22’23 Similarly, RV/TLC is elevated in

the absence of decreased expiratory flow rates in

early small airway obstruction.’6’2224 Thus, all of

the observed pulmonary function abnormalities

suggest small airway obstruction.

Small airway obstruction can result from loss of

elastic recoil or intrinsic airway obstruction. Elastic

recoil was not measured in this study. However, the

closing volume is a reflection of elastic recoil in

pediatric patients.25’26 Closing volume was normal

in nearly all patients, suggesting that elastic recoil

was not significantly decreased. Iron deposition has

been observed on postmortem examination of the

mucous membranes of airways from patients

re-ceiving multiple blood transfusions.’3 However, iron

was specifically noted to be absent from elastic

tissue and reticulum of the lung parenchyma,’3

sug-gesting that elastic recoil would not be affected.

Iron deposition in the airway lining may cause

intrinsic airway obstruction.

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rily to iron deposition, a defect related to the basic

disease, or a combination of the two cannot be

determined from this study. All patients in this

study received hypertransfusion therapy for 6.8 ±

0.6 years. Pulmonary function abnormalities did not

correlate with age or the cumulative amount of iron

received via blood transfusions. Life expectancy has

not decreased on hypertransfusion therapy,

sug-gesting that tissue damage from iron deposition is

dependent on factors other than the amount of

blood transfused alone.9’27’28 At least for the

myo-cardium, tissue hypoxia may also be neccesary for

destructive changes due to iron deposition. Thus,

the failure of pulmonary function abnormalities to

correlate with age or cumulative iron via blood

transfused may relate to intrinsic variation in the

expression of disease and/or individual differences

in iron metabolism and tissue hypoxia.

SUMMARY

Pulmonary function tests were performed on 12

patients with thalassemia major receiving

hyper-transfusion therapy. Only one patient had

corn-pletely normal pulmonary function. Hypoxia at rest

was present in ten of 12 patients (83%).

Hyperinfla-tion was present in five of 12 patients (42%).

De-creased expiratory flow rates of 60% TLC was

pres-ent in four of 12 patients (33%). Total lung capacity,

closing volume, and single breath diffusing capacity

were normal in all patients. These results suggest

the presence of small airway obstruction. This may

be due to iron deposition in the small airways or to

a defect associated with the basic disease.

ACKNOWLEDGMENTS

This project was supported in part by UNICO San

Gabriel Valley Chapter, Los Angeles Chapters of the

Italian Women’s Club, Seniors and Juniors and Pugliese

Lodge No. 1357 of the Sons of Italy.

The authors wish to thank Mr Stuart Foster and Ms

Daisy Bautista for their technical assistance; Michael Armour, Katherine Wilson, RN, and Theresa Varatta,

RN, for their participation in this project; and Ms

Vin-cenzina Sciortino for preparation of the manuscript.

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1980;65;1013

Pediatrics

Platzker

Thomas G. Keens, Margaret H. O'Neal, Jorge A. Ortega, Carol B. Hyman and Arnold C.G.

Program