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\begin{document}

\title{Pulmonary dysfunction in childhood Hodgkin lymphoma survivors: An
observational study}



\author[1]{Praneetha Mude}%
\author[2]{Rachna Seth}%
\author[2]{Jagdish Meena}%
\author[3]{Aditya Gupta}%
\author[1]{Sushil Kabra}%
\author[2]{Sumita Gupta}%
\author[2]{SN Dwivedi}%
\author[1]{Devasenathepathy Kandasamy}%
\affil[1]{AIIMS}%
\affil[2]{All India Institute of Medical Sciences}%
\affil[3]{Childrens Hospital at Westmead}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Childhood cancer survivors are 8.8 times more likely to die
of pulmonary causes when compared to general population: an aspect of
concern. Pulmonary dysfunction is the third leading cause of non
recurrence related cause of death among Hodgkin lymphoma survivors.
Methods: A cross section study on Hodgkin lymphoma survivors in complete
remission, who completed treatment within last 5 years was done. All
children were subjected to detail history including drugs, past history
of respiratory illnesses, physical and respiratory system examination
followed by spirometry and three minute step test under supervision.
Pulmonary dysfunction was determined as presence of obstructive,
restrictive or mixed pattern on spirometry or abnormality in three
minute step test. Subclinical pulmonary dysfunction was determined as
patients who were clinically asymptomatic but had pulmonary dysfunction
Results: A total of 60 children were enrolled (Mean age of 11.3 years
and 53 were boys) Abnormal pulmonary function tests were documented in
11 (18.3\%) of HL survivors at a median time of 2 years (IQR 1,3) from
treatment completion. Restrictive pattern was documented in 10 (16.67\%)
and obstructive pattern in only one patient (1.67\%), mostly mild in
severity. Older age at start of chemotherapy and radiotherapy and past
history of respiratory illness were found to be significantly associated
with pulmonary dysfunction. Conclusion: Majority of Hodgkin lymphoma
survivors had subclinical pulmonary dysfunction at median follow up of 2
years from treatment completion. Hodgkin lymphoma survivors require long
term follow up for timely detection of pulmonary dysfunction and improve
quality of life.%
\end{abstract}%



\sloppy


\textbf{TITLE PAGE}

\textbf{Title} : Pulmonary dysfunction in childhood Hodgkin lymphoma
survivors: An observational study

\textbf{Affiliations of authors} :

Dr Mude Praneetha :Senior Resident Department of Pediatrics, AIIMS, New
Delhi

Dr Rachna Seth : Professor, Department of Pediatrics, AIIMS, New Delhi

Dr Jagdish P Meena :Associate Professor, Department of Pediatrics,
AIIMS, New Delhi

Dr Aditya K Gupta : Assistant Professor, Department of Pediatrics,
AIIMS, New Delhi

Dr SK Kabra : Professor, Department of Pediatrics, AIIMS, New Delhi

Dr Sumita Gupta : Senior Physiotherapist, Department of Pediatrics,
AIIMS, New Delhi

Dr SN Dwivedi : Professor, Department of Biostatistics, AIIMS New Delhi

Dr Devasenathipathy : Additional Professor, Department of
Radiodiagnosis, AIIMS New Delhi

\textbf{Corresponding author details:}

Name : Dr Rachna Seth

Phone no : 9971188687

Email id : drrachnaseth1967@gmail.com

Permanent address: Room3063,Third Floor

Department of Pediatrics, AIIMS

\textbf{Abstract word count :} 249

\textbf{Main text word count :}2484

\textbf{Number of tables :} 05

\textbf{Number of references} : 12

\textbf{Conflict of interest} : None

\textbf{Funding} : None

\textbf{Role of authors} : Praneetha Mude designed the study, collected
data, and wrote the manuscript. SP did this study as a part of the
requirement for the degree of MD Paediatrics. Dr Rachna Seth was chief
guide for this study, and she supervised the study design, data
collection, and manuscript writing. Dr Aditya K Gupta, Dr JP Meena, Dr
SK Kabra and Dr Devasenathipathy supervised the whole study. Dr SN
Dwivedi calculated the sample size and supervised statistical analysis.
Dr Sumita Gupta supervised three minute step test which is used a
parameter to define pulmonary dysfunction. All the authors reviewed and
approved the manuscript.

\textbf{Key words :} Childhood, Hodgkin lymphoma survivors, pulmonary
dysfunction chemotherapy, radiotherapy

\textbf{Abbreviations key}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Abbreviation} & \textbf{Full phrase}\tabularnewline
\midrule
\endhead
HL & Hodgkin Lymphoma\tabularnewline
ABVD & Adriamycin, Bleomycin, Vinblastine, Dacarbazine\tabularnewline
BEACOPP & Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide,
Vincristine, Procarbazine, Prednisone\tabularnewline
FEV1 & Forced expiratory volume in 1 second of predicted\tabularnewline
FVC & Forced vital capacity\tabularnewline
mMRC & Modified Medical research council\tabularnewline
IFRT & Involved field radiotherapy\tabularnewline
TB & Tuberculosis\tabularnewline
ATT & Antitubercular therapy\tabularnewline
PFT & Pulmonary function test\tabularnewline
\bottomrule
\end{longtable}

\textbf{Abstract}

\textbf{Background:} Childhood cancer survivors are 8.8 times more
likely to die of pulmonary

causes when compared to general population: an aspect of concern.
Pulmonary dysfunction is the third leading cause of non recurrence
related cause of death among Hodgkin lymphoma survivors.

\textbf{Methods:} A cross section study on Hodgkin lymphoma survivors in
complete remission, who completed treatment within last 5 years was
done. All children were subjected to detail history including drugs,
past history of respiratory illnesses, physical and respiratory system
examination followed by spirometry and three minute step test under
supervision. Pulmonary dysfunction was determined as presence of
obstructive, restrictive or mixed pattern on spirometry or abnormality
in three minute step test. Subclinical pulmonary dysfunction was
determined as patients who were clinically asymptomatic but had
pulmonary dysfunction

\textbf{Results:} A total of 60 children were enrolled (Mean age of 11.3
years and 53 were boys) Abnormal pulmonary function tests were
documented in 11 (18.3\%) of HL survivors at a median time of 2 years
(IQR 1,3) from treatment completion. Restrictive pattern was documented
in 10 (16.67\%) and obstructive pattern in only one patient (1.67\%),
mostly mild in severity. Older age at start of chemotherapy and
radiotherapy and past history of respiratory illness were found to be
significantly associated with pulmonary dysfunction.

\textbf{Conclusion} : Majority of Hodgkin lymphoma survivors had
subclinical pulmonary dysfunction at median follow up of 2 years from
treatment completion. Hodgkin lymphoma survivors require long term
follow up for timely detection of pulmonary dysfunction and improve
quality of life.

\textbf{Keywords: Childhood, Hodgkin lymphoma survivors, pulmonary
dysfunction chemotherapy, radiotherapy}

\textbf{Introduction}

In the current era, newer chemotherapeutic agents have drastically
improved 5 year survival rate of Hodgkin Lymphoma (HL) to 90\% (1).
However these treatment advances are associated with long term effects
of which pulmonary dysfunction is the third leading cause of
nonrecurrence related cause of death among HL survivors (2). Pulmonary
dysfunction seen in HL survivors can develop secondary to chemotherapy
or radiotherapy (3). Bleomycin is a known pulmonary toxin among the
chemotherapy drugs used in treatment of HL The possible mechanism of
bleomycin induced lung injury include i) oxidative damage from reactive
oxygen species leading to fatty acid oxidation ,membrane instability and
inflammatory reactions in the lung. ii) relative deficiency of
metabolizing enzyme bleomycin hydrolase in the lung iii) genetic
susceptibility iv) elaboration of inflammatory cytokines (4). Radiation
induced lung injury can be acute radiation pneumonitis or chronic
radiation induced pulmonary fibrosis (5).

Most of the studies on pulmonary dysfunction in Hodgkin lymphoma
survivors till date are conducted in adult population of childhood
Hodgkin lymphoma survivors. (6). With respect to pulmonary dysfunction
in HL survivors, there is paucity of literature regarding prevalence,
clinical manifestations and pattern (obstructive/restrictive) of
abnormalities in pulmonary function tests (2,7). The studies conducted
so far on pulmonary dysfunction have been on heterogenous population
(2,7). The present study was undertaken to evaluate the prevalence,
spectrum and risk factors for occurrence of pulmonary dysfunction in
Indian childhood survivors of Hodgkin lymphoma

\textbf{Methods}

All biopsy proven HL survivors of age 6-18 years, within 5 years of
treatment completion and in complete remission attending Pediatric
cancer survivor clinic (PCSC) at tertiary care center in New Delhi were
enrolled for the study. The demographic details of the patients,
clinical pulmonary symptoms (chronic cough, breathlessness), grade of
dyspnea according to Modified Medical research council (mMRC scale) past
history of respiratory illness (asthma/recurrent nebulisations in the
past/ tuberculosis/pneumonia), treatment history including chemotherapy
related- regimen used (ABVD/BEACOPP), number of cycles, cumulative dose
of bleomycin, cyclophosphamide, Adriamycin and dacarbazine, radiotherapy
related-site, dose and fraction of radiation received, disease related
history (primary presentation, site of involvement, bulky disease, stage
and B symptoms) were recorded in a structured proforma. A detailed
physical examination was done for all patients, Vitals (including SpO2)
and anthropometry were recorded in detail. Nutritional status was
assessed. Respiratory system examination was done in detail. Relevant
investigations including hemogram at the time of evaluation, and
previous echocardiography findings of ejection fraction was collected.
Pulmonary function was evaluated by spirometry and 3 minute step test.
Pulmonary dysfunction was determined as presence of obstructive,
restrictive or mixed pattern on spirometry or abnormality in three
minute step test. Subclinical pulmonary dysfunction was determined as
patients who were clinically asymptomatic but had pulmonary dysfunction
on spirometry or three minute step test

\textbf{Spirometry}

Spirometry was performed by a portable spirometer, spirolab (Medical
International Research, Rome, Italy) which is standardised for Indian
children (based on height) in Paediatric OPD AIIMS, New Delhi during
follow up visits. Forced expiratory volume in 1 second of predicted
(FEV1), forced vital capacity (FVC), FEV1/FVC ratio were assessed after
obtaining acceptable spirometry curves. Abnormal pulmonary function is
determined as presence of obstructive, restrictive or mixed pattern on
spirometry or abnormality in three minute step test. Obstructive pattern
is defined as having forced vital capacity of percent predicted [?]80\%
and FEV1/FVC \textless{}85\%. Restrictive pattern is defined as having
forced vital capacity of percent predicted \textless{}80\% and FEV1/FVC
[?]85\%. Mixed pattern is defined as having forced vital capacity of
percent predicted \textless{}80\% and FEV1/FVC \textless{}85\%. Based on
FEV1, severity of obstructive pattern was assessed as mild, moderate,
moderately severe, severe or very severe obstruction if predicted FEV1
is \textgreater{}70\%, between 60\% to 69\%, between 50\% to 59\%,
between 35\% to 49\%, \textless{}35\% respectively. Based on FVC,
severity of restrictive pattern was assessed as mild, moderate, severe
or very severe obstruction if predicted FVC is \textgreater{}70\%,
between 50\% to 69\%, between 35\% to 49\%, between, \textless{}35\%
respectively

\textbf{Three minute step test}

All the subjects were asked to step up and down a 15cm high single step
at a rate of 30 steps per minute regulated by a metronome. Pre and post
test heart rate and saturation (SpO2) were recorded by pulse oximetry
after obtaining appropriate wave form. Only one attempt was offered per
child and if unable to complete the test then reason for stopping was
also recorded

\textbf{Statistical analysis:}

Descriptive statistics were used for analysing demographic, treatment
and disease characteristics. Quantitative variables are presented as its
mean (SD) and qualitative variables as frequency (\%). Pulmonary
function test was classified as dichotomous variables-normal and
abnormal. The prevalence of pulmonary function abnormalities is
presented as frequency (\%). The associated factors were also classified
as dichotomous variables. Age at evaluation, age at start of
chemotherapy and age at start of radiotherapy as [?] 10 years and
\textgreater{}10years.Cumulative bleomycin dose was categorised as
[?]80mg/m2 (1mg=1IU) and \textgreater{}80mg/m2. The associations of
categorical variables with abnormal pulmonary function was assessed
using chi-square/ Fisher's exact test. A p-value less than 0.05 was
considered as statistically significant. Regression analysis and
multivariable analysis couldn't be carried out due to less event rate in
our study sample. Analysis was done by stata14.

\textbf{Results:}

In this cross sectional study, performed from January 2019 to December
2020, 72 Hodgkin lymphoma survivors were screened and 60 were enrolled.
Ten children were excluded as they had completed treatment beyond 5
years of enrolment and two children were excluded as they were above 18
years of age.

Patient and disease characteristics are listed in table 1. The mean age
of the study population was 11.3 years with SD of 2.77. Majority were
males. Only three (5\%) patients had clinical symptoms of dyspnea on
exertion and three (5\%) patients had decreased air entry on one side on
auscultation. Out of 60 patients, 57 (95\%) received ABVD regimen, at
mean age of 8.6 years, median cumulative dose of bleomycin 120mg/m2
(range 30-120mg/m2). Only three patients (5\%) received cyclophosphamide
in their chemotherapy regimen. Eighteen patients (30\%) received
involved field radiotherapy (IFRT) along with chemotherapy at median age
of 10.75 years, 9 (15\%) received IFRT to mediastinum with dose of
25-30Gy(4 patients received 25Gy and 5 patients received 30 Gy) and 15
fraction. Median time to assess pulmonary function post completion of
treatment was 2 years. Lab parameters such as hemoglobin and total
leucocyte count were normal in all patients. Only 2 patients (3.33\%)
had ejection fraction of less than 60\%

\textbf{Pulmonary function tests :}

All the sixty subjects were able to perform spirometry, of which
abnormal pulmonary function test was present in 11 (18.33\%) of studied
HL survivors.

Restrictive pattern was seen in 10 (16.67\%) of patients and obstructive
pattern was seen in

1(1.67\%) of patients. Most of them had mild severity of abnormal PFT.
One patient who had

obstructive pattern had mild obstruction. Of 10 patients with
restrictive pattern, 7 (11.66\%)

had mild restriction and 3 (5\%) had moderate restriction. Parameters
and PFT are described in table 2

\textbf{Three minute step test :}

All the 60 HL survivors were able to complete three minute step test.
Median pre and post

test saturation 98 and 98 respectively, signifying that there was no
desaturation post 3 minute

step test. Mean pre and post test heart rate are 90.5\selectlanguage{ngerman}±15.44 and
127.5±19.50 respectively. Post

test heart rate for all the patients were within the expected rise in
heart rate post exertion (i,e

69\% predicted maximal heart rate to 80\% of predicted maximal heart
rate) (31,32).

Predicted maximal heart rate was measured by Tanaka equation (Predicted
maximal heart

rate = 208-0.7*age) (33). Parameters of 3 minute step test are detailed
in table 3.

Normal and abnormal pulmonary function tests of the patients were
compared, children

above age of 10 years at evaluation had higher percentage (90.91\%) of
abnormal PFT when

compared to children of age less than 10 years (9.09\%) at evaluation
(p=0.043). Patients with significant respiratory illness in the past was
found to a be statistically significant associated factor for pulmonary
dysfunction (p=0.017) Patients who received radiation had

higher percentage (54.55\%) of abnormal PFT than patients who did not
received radiotherapy

(45.45\%) (p=0.071). Patients who received involved field radiation to
mediastinum shows a

trend towards developing abnormal PFT (p=0.064). Patients who received
chemotherapy and

radiation at age of less than 10 years had higher percentage (54.55\%
and 36.36\%

respectively) of abnormal PFT than patients of age less than 10 years
(45.45\% and 18.18\%

respectively) (p=0.030, p=0.075 respectively). Associated factors for
pulmonary dysfunction

are described in table 4.

Patients who received chemotherapy (bleomycin cumulative dose of
\textgreater{}80mg/m2) and

radiotherapy had higher percentage (54.55\%) of abnormal PFT than
patients who received

only chemotherapy (bleomycin cumulative dose of \textgreater{}80mg/m2)
(13.33\%).

\textbf{Discussion:}

We studied pulmonary dysfunction (prevalence, spectrum and risk factors
for occurrence) and pattern of respiratory dysfunction in
childhoodHodgkin lymphoma survivors from India.

The prevalence of abnormal pulmonary function test in our study was
18.33\% (11 of 60)

which is comparable to two pediatric studies done in homogenous group of
Hodgkin

lymphoma, 17.3\% in a study by agrusa et al (9) and 13\% in a study by
Venkatramani et al

(8) in which only effect of radiotherapy was evaluated.

Bleomycin is known to cause pulmonary fibrosis by various mechanism and
results in

restrictive lung disease (4). Radiotherapy to chest causes either acute
radiation pneumonitis

or chronic pulmonary fibrosis leading to development of restrictive lung
disease (5). As both

bleomycin and radiotherapy are part of treatment regimen in Hodgkin
lymphoma, it is known

that they develop restrictive lung disease in long term. This was
evident in our study, in

which prevalence of restrictive pattern (16.67\%) of PFT was higher than
obstructive (1.67\%)

pattern and mostly mild (13.33\%) in severity, consistent with data from
St Jude life time

cohort study though it was done in a heterogenous group, majority of the
study population

were survivors of Hodgkin lymphoma (49.3\%) (10)

Though 11 (18.33\%) patients had abnormal PFT, only 2 (3.33\%) patients
had clinical

symptoms i,e dyspnea on exertion and 3 (5\%) patients had decreased air
entry on auscultation

of lung fields at the time of evaluation. Our data is consistent with
previous studies done by

Zorzi et al who reported 41\% with abnormal PFT but only 8\% had
clinical symptoms (2).

Another study done by Aliva et al reported at least one pulmonary
function abnormality in

52.5\% but clinical symptoms were present only in 8.7\%. This signifies
higher burden of sub

clinical pulmonary dysfunction and thus need for routine pulmonary
function assessment

during follow up of HL survivors.

Our study identified pulmonary dysfunction at a median time of 2 years
from completion of

treatment, suggesting early development of pulmonary dysfunction and
need for timely

follow up and intervention, similar to most of the studies (2,7,8,9).

Most of the studies conducted till date determined either effect of
bleomycin or radiotherapy on pulmonary dysfunction in a heterogenous
population (2,7,10). To best of our knowledge there are only two
pediatric studies done in homogenous population of Hodgkin lymphoma
survivors to determine the associated factors for development of
pulmonary dysfunction

(8,10). In our study, higher age at time of treatment (chemotherapy
and/or radiotherapy) i,e age \selectlanguage{english}[?] 10years at the time of treatment was
associated with development of abnormal PFT. Similar to study done by
Venkatramani et al (8) and Azza et al (12). Supporting higher age at
start of treatment associated factor for development of pulmonary
dysfunction in our study we found that children of age \textgreater{} 10
years at evaluation had higher risk (90.91\%) of abnormal pulmonary
function when compared to children of age \selectlanguage{english}[?] 10 years (9.09\%) (p=0.043).
This could be explained by reduction in lung capacity as age progresses
and loss of repairing ability as age progresses.

In children bleomycin induced lung injury is reported usually at a dose
above 120mg/m2 (2)

, concomitant thoracic irradiation and other chemotherapeutic agents
like cyclophosphamide

can cause pulmonary dysfunction at lower doses. In our study we
demonstrated a higher risk

of pulmonary dysfunction in survivors who received combined chemotherapy
and radiation (54.55\%) when compared to survivors who received
chemotherapy alone (13.33\%), comparable to previous studies (10,11).
Most of the survivors i,e 57 (95\%) received ABVD as chemotherapy
regimen, 2 patients received BEACOPP and one patient received ABVD

alternating with COPP regimen. Median cumulative dose of bleomycin was
120mg/m2 (range 30-120mg/m2). Receiving radiotherapy was shown to have
higher association with

development of pulmonary dysfunction when compared to chemotherapy alone
i,e bleomycin

at a median dose of 120mg/m2.

It is interesting to note that of two patients who received BEACOPP
regimen, one patient

who received cumulative bleomycin dose of 80 mg/m2 and cumulative
cyclophosphamide

dose of 5200 mg/m2 with decreased ejection fraction (\textless{}60\%) on
echocardiography,

developed restrictive pattern on spirometry at a median follow up of 4
years. Other patient

who received cumulative bleomycin dose of 70 mg/m2 and cumulative
cyclophosphamide

dose of 4550 mg/m2 with normal ejection fraction on echocardiography had
normal

spirometry at a median follow up of 1 year from completion of treatment,
signifying presence

of underlying cardiac dysfunction, an associated factor for development
of pulmonary

dysfunction and need for evaluation of the same especially when
concomitant cardiotoxic

chemotherapeutic drugs are given during therapy also longer period of
follow up which may

unfold pulmonary dysfunction.

To assess functional status of HL survivors we did 3 minute step test.
In our study all

survivors were able to complete 3 minute step test, had expected rise in
heart rate and no desaturation post three minute test. This could be
because most of the survivors had mild pulmonary dysfunction which might
not cause functional limitation, other reason could be use of same 15 cm
height step irrespective of patient's age. However these children would
require long term follow up as severity of pulmonary dysfunction may
progress with time.

Strengths of our study are, we did a prospective study in a homogenous
group of childhood Hodgkin lymphoma survivors and assessed effect of
both chemotherapy and radiotherapy.

However, our study had certain limitations, we did not have baseline
pulmonary function

assessment prior to start of treatment and there were no controls. DLCO
could not be done in our study population which could have demonstrated
higher proportion of subclinical pulmonary dysfunction as seen in
previous studies (9).

Majority of Hodgkin lymphoma survivors had subclinical pulmonary
dysfunction

(Clinically asymptomatic but had pulmonary dysfunction on spirometry or
three minute step test) at median follow up of 2 years from treatment
completion. As the survival rate of HL patients has improved, during
this life time children can be exposed to environmental hazards like
smoke, pollution which can accelerate the deterioration of pulmonary
function. Therefore Hodgkin lymphoma survivors require thorough initial
assessment of respiratory status and pulmonary function testing and long
term follow up for timely detection of pulmonary dysfunction and improve
quality of life.

\textbf{Conflicts of interests} : None to declare by any of the authors.
The authors alone are responsible for the content and writing of the
paper.

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\textbf{Hosted file}

\verb`TABLE 5 Comparison of PFTs in patients who received combined chemotherapy and.docx`  available at \url{https://authorea.com/users/472538/articles/563299-pulmonary-dysfunction-in-childhood-hodgkin-lymphoma-survivors-an-observational-study}

\selectlanguage{english}
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