Original Article

Pulmonary Function Tests in Beta Thalassemia

Meeta Arora, Jagdish Chandra, J.C. Suri, 1 S. Narayan 2 and A.K. Dutta

IDepartment of Pulmonary and Critical Care Medicine, Safdarjang Hospital and Departments of
Pediatrics and 2Pathology, Lady Hardinge Medical College and Kalawati Saran Children's Hospital,
New Delhi

Abstract. To study pulmonary function tests (PFT) in multiple transfusion recipient thalassemics, PFTs were done
for 30 thalassemics and 20 matched controls. Confirmed cases of thalassemia on regular transfusion therapy were
the subject of study. Apart from history and physical examination of the thalassemi.cs, serum ferritin estimation and
spirometry were done. Parameters studied included lung volumes--functional residual capacity (FRC), forced vital
capacity (FVC), residual volume (RV) and total lung capacity (TLC); and flow rates - forced expiratory volume in
one second (FEV1), forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC), peak expiratory flow
25-75 (PEF 25-75%) and peak expiratory flow rate (PEFR). Single breath carbon monoxide diffusing capacity
(DLco) and arterial blood gas (ABG) were also analysed. The mean height and weight of thalassemics were below
that of age matched controls. A restrictive abnormality in PFT was found in 86.6% cases. These patients were found
to have a decrease in all the lung volumes namely FVC, FRC, RV and TLC with a proportional decrease in the flow
rates, FEV1, PEF 25-75% and PEF with a normal (> 0.75) FEV1/FVC ratio. DLco was decreased in all the patients
with restrictive lung disease and fall in DLco showed a good correlation (r = 0.7, P < .001) with the severity of
restrictive disease suggesting that some intrapulmonary pathology is likely to be responsible for the restrictive
pattern. None of the cases had an obstructive or mixed pattern of pulmonary dysfunction. No correlation was found
between severity of restrictive disease and the serum ferritin levels. A negative correlation with degree of
hepatosplenomegaly was found. No correlation was found between severity of the defect and age, number of blood
transfusions received and hemoglobin at the time of doing the test. To conclude, restrictive lung disease is the
predominant abnormality in multi-transfused thalassemics, which is probably due to pulmonary parenchymal
pathology. The abnormality of PFTs is not directly related to iron overload.
[Indian J Pediatr 2001; 68 (3) : 239-242]

Key words : Pulmonary function tests; Thalassemia; Lung volumes.

The life span of thalassemics has increased
considerably due mainly to regular blood transfusion
therapy. Unfortunately most patients still succumb in
the second decade of life to the side effects of iron
overload which have been associated with damage to
various organ systems of the body. 1-3Chelation therapy
required to decrease the iron overload is out of reach of
many due to economic and other reasons. Thalassemics
who are not on the h y p e r t r a n s f u s i o n regime
demonstrate the effects of chronic hypoxia like growth
retardation and extramedullary hematopoeisis which
is characterized by hepatosplenomegaly and skeletal
changes.
No study is available in Indian literature regarding
the pulmonary function abnormalities in thalassemics.
Reprint requests : Jagdish Chandra, 10, Lecturer's Flats, Lady
Hardinge MedicalCollegeCampus, BanglaSahib Road, New
Delhi-110 001. E-mail : jagdish@pediaindia.net
Indian Journal of Pediatrics, 2001; 68 (3) : 239
Those carried out abroad are contradictory - some
demonstrating a restrictive and others an obstructive
pulmonary function abnormality.4~Because of paucity
of data from our country, this work was planned to
highlight the pulmonary function tests in thalassemics
in our country as most of them are still not on
hypertransfusion regimen and regular chelation.
MATERIALS AND METHODS
The study was carried out from April 1997 to March
1998 on patients of beta thalassemia major above the
age of 8 years who were on regular blood transfusion
programme. The diagnosis of thalassemia had been
confirmed by hematological examination including
hemoglobin electrophoresis. Most of the patients were
receiving/had received iron chelation therapy with
desferoxamine and /or deferiprone but this was not
regular due to financial constraints. Patients with
 M. Arora et al
history of asthma in themselves or in the family and
other obvious acute or chronic respiratory disease were
excluded. A Mantoux test and chest X-ray was done
for t u b e r c u l o s i s and those w i t h i n v e s t i g a t i o n s
suggestive of tuberculosis were also excluded. Of the
37 eligible patients, 7 were excluded (4 for family
history of asthma, I for having pulmonary tuberculosis
and 2 because of not being able to perform spirometry
satisfactorily). Thus 30 patients were included after
informed consent of the parents was obtained.
A c o m p l e t e h i s t o r y and t h o r o u g h p h y s i c a l
examination was done to rule out any acute respiratory
problem that might interfere with pulmonary functions
and oxygenation. The number of transfusions and
mean hemoglobin maintained during previous six
months were recorded. P u l m o n a r y function tests
(PFTs) w e r e p e r f o r m e d 48 h o u r s after the b l o o d
transfusion by using Morgan's Transfer Test system
Model C. The flow rates (FEV,, PEF25_75O/o,PEF) were
studied using spirometry and various volumes and
capacities (FVC, FRC, RV, TLC) were measured using
Helium dilution technique. The following parameters
were recorded :
FEV1 Forced expiratory volume in one second.
PEF 25.75% Forced expiratory flow rate from 25% - 75%
of vital capacity.
FRC Functional residual capacity.
FVC Forced vital capacity.
FEV1/FVC - Forced expiratory volume in one second/
forced vital capacity.
PEF Peak expiratory flow.
RV Residual volume.
TLC Total lung capacity.
VC Vital capacity.
DLco Single breath carbon monoxide diffusing
capacity.
DLco was measured using single breath method.
The apparatus on which the PFTs were studied
expressed the results as percentage of normal, still it
was felt necessary to have PFTs of normal controls of
the same ethnic groups. 7Therefore PFTs of 20 age and
sex m a t c h e d controls w e r e also s t u d i e d for
comparison.
Assessment of iron overload was done by estimating
serum ferritin levels b y ELISA m e t h o d using UBI
Magiwel TM kit. The results were statistically analysed
using Student's-t test and co-efficient of correlation (r).
RESULTS
The mean age of study group 11.83 _+1.91 years (range
9-17 years) and that of control group 12.25 + 2.17 years
240
(range 9-17 years) was comparable. The male and
female ratio in both the groups was I : 1. Mean height
and weight of the study group was significantly lower
than that of control group (data not shown). Mean
hemoglobin of the patients was 9.87 + 1.45 gm / dl and
mean serum ferritin level was 3975 + 870.7 ng/ml.
Table 1 and 2 s h o w the results of PFTs in both
g r o u p s . It is e v i d e n t that s t u d y g r o u p s h o w e d a
significant decrease in all lung volumes i.e. FVC, FRC,
RV and TLC and a proportionate decrease in the flow
rates i.e. FEV1, PEF2s.75O/ocompared to control group
(P < .001). Mean FEV1/FVC was greater than 0.75 in all
cases. Analysis of PFTs in each individual case showed
that 26 out of 30 patients 86.6% had restrictive airway
disease. This was concluded from the fact that all these
26 cases had significantly reduced RV, FVC and TLC
but the FEV-/FVC was greater than 75%. Obstructive
or mixed airway disease pattern was not observed in
any case as RV was either normal or reduced and
FEV~ / FVC was not lower than 75%.
The subjects with restrictive airway pattern were
classified for severity based on reduction in FVC (mild,
FVC 60-79%; moderate, FVC 40-59% and severe, FVC
< 40%). O u t of the 26 cases w i t h restrictive
abnormality, 11 (42%) patients had mild and 15 (58%)
patients had moderate abnormality. Severe restriction
was not observed in any case.
DLco was reduced in the study group significantly
(P < .001). There w a s strong positive correlation
b e t w e e n DLco and FVC and thus the severity of
restrictive pattern (r -- 0.7, P < .001). Restrictive pattern
s h o w e d negative correlation with h e p a t o m e g a l y
(r=0.62, P< 0.001) and splenomegaly (r=0.36, P< 0.05).
The restrictive p a t t e r n did not s h o w significant
correlation with age of the patient, (r--0.12, P--0.93)
number of transfusions received (r = 0.16, P = 0.84) and
hemoglobin in previous 6 months (r -- 0.14, P=0.45).
With serum ferritin also only a weak correlation was
observed (r = 0.05, P--0.07).
DISCUSSION
Several investigators have attempted to characterise
the p u l m o n a r y d y s f u n c t i o n in t h a l a s s e m i c s and
establish its etiology. D e s p i t e these efforts,
TABLE1. Lung Volumes in Study and Control Groups
Group FVC FRC RV TLC
Study 63.60 58.27 57.57 69.03
+ 15.16 + 13.06 + 17.72 + 12.42
Control 88.40 88.60 85.55 89.10
+ 6.01 + 6.54 + 4.67 + 6.97
P value < .001 <.001 <.001 <.001
Indian Journal of Pediatrics, 2001; 68 (3)
 Pulmonary Function Tests in Beta Thalassemia
TABLE2. Flow Rates and Dlco in Study and Control Groups
Group FEV1 PEF25.75
Study 59.60 56.47
• 19.09 + 20.02
Control 86.05 84.80
• 4.82 • 4.75
P value < .001 <.001
controversies exist about the nature of dysfunction and
its pathogenesis. In the largest n u m b e r of patients
evaluated to date we have documented that the most
striking abnormality is a reduction in lung volumes
indicative of a restrictive p a t t e r n of p u l m o n a r y
dysfunction. As the fall in flow rates is proportionate in
restrictive lung d y s f u n c t i o n FEV 1 / FVC remains
normal i.e. greater than 0.75. 8,9All the patients in our
series had FEVi/FVC of greater than 0.75.
Our findings contrast with those of Keens et al and
H o y t et al, w h o r e p o r t e d airway obstruction and
h y p e r i n f l a t i o n in their t h a l a s s e m i a patients. 4,6
However, in both these series there was no decrease in
expiratory flow indices and FEV~ /FVC ratio were as
high as 0.82 and 0.90 respectively. This ratio can be
taken as a sole criteria for classifying p u l m o n a r y
d y s f u n c t i o n and its decrease to less than 0.75 is
suggestive of obstructive p u l m o n a r y dysfunction 8
which was not the case in these two series.
Our results support the findings of Cooper et aI who
reported restrictive pattern with low diffusion capacity
in 70% of their patientsd Recently, Grisaru et aI and
Factor et al in their studies have also o b s e r v e d a
restrictive pattern of lung function 'abnormalities in
70% of their patients, l~
Several factors relevant to thalassemia and its
t h e r a p y m a y be r e s p o n s i b l e for d e v e l o p m e n t of
pulmonary function abnormalities in patients with this
condition. Despite the fact that iron has been identified
h i s t o l o g i c a l l y in the p u l m o n a r y p a r e n c h y m a of
thalassemics, a cause and effect relationship has not
been established.
Serum ferritin values which are known to directly
correlate with liver iron content, did not show a good
linear correlation with pulmonary dysfunction in our
cases. Similar observations have been made earlier
also. 6A2Factor et al observed a significant correlation of
serum ferritin with total lung capacity. They felt that
degree and duration of iron overload both may be
important and postulated that iron may be responsible
for this dysfunction, through a free radical induced
injury n. However, Luyt et al observed no correlation of
pulmonary dysfunction with free oxygen radical status
Indian Journal of Pediatrics, 2001; 68 (3)
PEF DLco
53.93 48.47
• 12.43 • 9.36
85.55 89.0
+ 4.41 • 7.41
<.001 <.001
in their patients. 12
E n l a r g e m e n t of liver and spleen m a y restrict
m o b i l i t y of d i a p h r a g m and m a y c o n t r i b u t e to
restrictive pulmonary dysfunction as is seen in patients
w i t h o t h e r i n t r a b d o m i n a l causes of d i a p h r a g m
elevation like pregnancy and pneumoperitoneum, s
Our patients showed a negative correlation of their
p u l m o n a r y d y s f u n c t i o n with liver and spleen
e n l a r g e m e n t . In p r e s e n c e of a b n o r m a l d i f f u s i o n
capacity, a primary pulmonary pathology appears the
most likely cause of pulmonary dysfunction. DLco also
showed good correlation with severity.
Hepatosplenomegaly may also be contributing partly
to the defect as has been postulated by others. 5,13
We conclude that restrictive pulmonary function
abnormality is the main pulmonary dysfunction in
multitransfused thalassemics. In conjunction with
cardiac dysfunction and presence of anemia, it may
cause significant morbidity in terms of poor physical
performance.
REFERENCES
1. Kattami CA, Kattami AC. Management of thalassemia:
Growth and Development, Vitamin supplementation
and vaccination. Seminars Hematol 1995; 32 : 269-279.
2. Zurlo MF, Destefano P, Borgna-Pignatti C et al.
Survival and causes of death in thalassemia major.
Lancet 1989; 2 : 27-30.
3. Gaba A, D'Souza P, Chandra J, Narayan S, Sen S.
Ocular changes in b thalassemia. Ann Ophthalm
Glaucoma 1998; 30 : 357-360.
4. Keens TG, Oneal MH, Ortega JA, Hymom CB, Platzkey
AG. Pulmonary function abnormalities in thalassemia
patients on a hypertransfusion programme. Pediatr
1980; 65 : 1013-1017.
5. Cooper DM, Mansel AL, Weiner MA et aI. Low lung
capacity and hypoxemia in children with thalassemia
major. Amer Rev Resp Dis 1980; 121 : 639-646.
6. Hoyt RW, Nina S, Wilmott RW, Cohen A, Schwartz E.
Pulmonary function abnormalities in homozygous b
thalassemia. J Pediatr 1986; 109 : 452-455.
7. Fung KP, Wun Chow OK, Yeungso S, Yuen PMP.
Pulmonary function in thalassemia major. J Pediatr
1987; 111 : 534-537.
241
 M. Arora et al
8. Pfaff JK, Morgan WJ. Pulmonary function in infants
and children. Pediatr Clin NAmet: 1994; 41 : 401-423.
9. Wall MA. Office pulmonary function testing. Pediatr
Clin N Amer 1984; 31 : 773-783.
10. Grisaru D, Rachmilewitz EA, Mosseri Met al. Cardio-
pulmonary assessment in beta-thalassemia major. Chest
1990; 98 : 1138-1142.
11. Factor JM, Pottipati SR, Rappaport I, Rasner IK, Lesser
ML, Giardina PJ. Pulmonary function abnormalities in
242
thalassemia and the role of iron overload. Amer J Resp
Crit Care Mod 1994; 149 : 1570-1574.
12. Luyt DK, Roode H, Dowdeswell RJ, van Rensberg AJ,
Reinach SG. Thalassemia : Lung function studies with
reference to iron studies and reactive oxidant status.
Pediatr Hematol Oncol 1993; 10 : 13-23.
13. Youngchaiyud P, Suthamsmai T, Fucharoen S et al.
Lung function tests in splenectomised ~ thalassemia/
HbE patients. Birth Defects. 1988; 23 : 361-370.
Indian Journal of Pediatrics, 2001; 68 (3)