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\begin{document}

\title{Outpatient Treatment of Lower Respiratory Tract Infections in Children
with Tracheostomy}



\author[1]{Parevi Majmudar}%
\author[1]{Don Sanders}%
\author[1]{Andrew  Beardsley}%
\author[2]{James Slaven}%
\author[1]{A. Ioana Cristea}%
\affil[1]{Riley Hospital for Children at Indiana University Health}%
\affil[2]{Indiana University School of Medicine}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
RATIONALE: Outpatient treatment of lower respiratory tract infection
(LRTI) in tracheostomy dependent children varies institutionally. The
objective of this study was to identify whether only increasing airway
clearance (AWC) increased the odds of hospitalization within 28 days of
treatment. Our hypothesis was that those treated with antibiotics were
less likely to be hospitalized. METHODS: We retrospectively reviewed
medical charts of children who were tracheostomy dependent between
2012-2019 and followed at our institution. We recorded recommendations
with each sick call, i.e. prescription of antibiotics and/or increase in
frequency of airway clearance. Generalized estimating equation models
were used to determine whether the recommendation to increase AWC
frequency was associated with an increased risk of hospitalization
within 4 weeks, as compared to the prescription of oral and/or inhaled
antibiotics. RESULTS: Of the eighty -two patients reviewed, there were
283 unique episodes of LRTI. 160 (45\%) episodes involved increasing AWC
alone and 195 (55\%) were given an antibiotic in addition to increasing
AWC. Of those who received AWC only, 21.7\% were hospitalized within 28
days of treatment, and 13.8\% were hospitalized after treatment with
increased AWC and oral/inhaled antibiotics, p= 0.08. Those who received
only AWC did not have significantly higher odds of hospitalization
within 28 days of treatment, compared to those who received an
antibiotic: adjusted OR 1.47 (95\% CI: 0.75, 2.86); p=.26. CONCLUSIONS:
In this retrospective cohort study of pediatric patients with
tracheostomy, a recommendation to increase airway clearance only versus
initiating an antibiotic was not associated with increased odds of
hospitalization.%
\end{abstract}%



\sloppy


Title: Outpatient Treatment of Lower Respiratory Tract Infections in
Children with Tracheostomy

Authors: Parevi Majmudar DO\textsuperscript{1}, D.B. Sanders
MD\textsuperscript{1}, Andrew Beardsley MD\textsuperscript{2}, James
Slaven MS\textsuperscript{3}, A. Ioana Cristea MD\textsuperscript{1}

\textsuperscript{1} Division of Pulmonary, Allergy and Sleep Medicine,
Riley Hospital for Children at Indiana University Health, Indianapolis,
IN

\textsuperscript{2}Division of Pediatric Critical Care Medicine, Riley
Hospital for Children at Indiana University Health, Indianapolis, IN

\textsuperscript{3} Department of Biostatistics, Indiana University
School of Medicine, Indianapolis, IN

Funding: None.

Meetings: This work will be presented at the virtual American Thoracic
Society meeting in 2020.

Correspondence: Parevi Majmudar, 705 Riley Hospital Dr, ROC 4270,
Indianapolis, IN 46202

Telephone: 317-948-0949, Fax: 317-944-5791

Email: Parevipm@gmail.com

Keywords: tracheitis, inhaled tobramycin, hospitalization, complex
medical conditions

Abstract

RATIONALE: Outpatient treatment of lower respiratory tract infection
(LRTI) in tracheostomy dependent children varies. The objective of this
study was to identify whether increasing frequency of airway clearance
(AWC) alone increased the odds of hospitalization within 28 days of
treatment. Our hypothesis was that those treated with antibiotics were
less likely to be hospitalized.

METHODS: We reviewed medical records of children who were tracheostomy
dependent between 2012-2019 and followed at our institution. We recorded
recommendations provided at each sick call or clinic visit, i.e.
prescription of antibiotics and/or increase in frequency of AWC, for
physician defined LRTI. Generalized estimating equation models were used
to determine whether the recommendation to increase AWC frequency was
associated with an increased risk of hospitalization within 4 weeks, as
compared to the prescription of oral and/or inhaled antibiotics.

RESULTS: Among the 82 patients reviewed, there were 283 unique episodes
of LRTI. Increasing AWC alone was recommended for 160 (45\%) episodes
and antibiotics were prescribed for 195 (55\%) in addition to increasing
AWC. Of those who received AWC only, 21.7\% were hospitalized within 28
days of treatment, compared to 13.8\% prescribed oral/inhaled
antibiotics, p= 0.08. Those who received AWC alone did not have
significantly higher odds of hospitalization within 28 days of
treatment: adjusted OR 1.47 (95\% CI: 0.75, 2.86); p=.26.

CONCLUSIONS: In this retrospective cohort study of pediatric patients
with tracheostomy, a recommendation to increase AWC alone was not
associated with increased odds of hospitalization compared to antibiotic
prescriptions.

\emph{Introduction}

An increasing number of critically ill children are surviving to
hospital discharge and tracheostomy placement has become more
widespread, often serving as a bridge from hospital to home. In addition
to tracheostomy, these children often have other comorbidities requiring
technology assistance including ventilators, gastrostomy tubes, vagal
nerve stimulators and cerebrospinal fluid shunts \textsuperscript{1}.

Despite the benefits of tracheostomy, rehospitalization is common, often
due to respiratory illness, major surgery, technology malfunction,
seizure or feeding difficulty \textsuperscript{1}. Hospitalizations for
children with tracheostomy account for over \$2.6 billion each
year\textsuperscript{2}. In 2019, the readmission rate for children on
home mechanical ventilation was 2.16 hospitalizations per patient in the
first year following discharge and average readmission cost was \$73,144
per patient \textsuperscript{3}. The length of stay was increased in
those with complex co-morbidities and in those who were younger at time
of admission \textsuperscript{2,4}. Respiratory diagnoses are still the
most frequent indications for admission \textsuperscript{2}, accounting
for more than 2000 admissions and \$100 million in hospital costs in
2009 \textsuperscript{4}.

Considering this high healthcare burden on families and resource
utilization, every effort is made to treat respiratory infections safely
at home. Even though there is a growing number of children with
tracheostomy, there is little published evidence regarding their chronic
care including identification and management of respiratory tract
infections \textsuperscript{5}. Since there are no guidelines for home
treatment of respiratory tract infections, choice of therapy varies by
institution and is practitioner driven.

The most common outpatient interventions include antibiotics (oral or
inhaled) and increasing frequency of airway clearance (AWC). In the
outpatient setting, it is often unclear if a patient would benefit from
antibiotics, and benefits must be weighed against risk associated with
antibiotics such as cost, drug-related side effects, and antibiotic
resistance. Due to the lack of natural upper airway humidification and
thicker secretions of patients with tracheostomy, providers may
recommend an increase in AWC therapies in an attempt to improve mucus
clearance and prevent or remedy infection.

Currently, there are no studies that evaluate the incidence of
hospitalization after outpatient treatment for lower respiratory tract
infections (LRTI) in children with tracheostomy. The objective of this
study was to identify whether there was a difference in risk of
hospitalization for LRTI within 28 days of treatment comparing
antibiotic prescription to increasing AWC alone. Our hypothesis was that
those treated with antibiotics were less likely to be hospitalized
following treatment.

\emph{Methods}

This was a single center retrospective study of patients with
tracheostomy who were followed at Riley Hospital for Children at Indiana
University Health from January 2012- December 2019. Eighty-two patients
were identified through review of internal tracheostomy and chronic
ventilator patient lists. Patients were included in the study if they
were tracheostomy dependent anytime between 2012-2019 and received
pulmonary outpatient care at Riley Hospital for Children. Patients were
excluded if they had a diagnosis of cystic fibrosis, primary ciliary
dyskinesia or malignancy, lived primarily at a long term care facility
or if they did not have any sick calls for respiratory illness.

For each patient, we reviewed all outpatient clinic visits, phone
messages recorded in the electronic medical record, emergency room (ER)
visits, and respiratory hospitalizations at Riley Hospital for Children
or other hospitals within the Indiana University Health system. We
gathered demographic data including sex, age and race. Tracheostomy
information including date of placement, date of initial hospital
discharge, date of ventilator liberation, and date of decannulation.
Respiratory cultures were collected via tracheal aspirate, blind
bronchoalveolar lavage (BAL) or bronchoscopic BAL were recorded. Blind
BAL samples are obtained by introducing a lavage catheter into the
artificial airway. The catheter is advanced into the distal airway until
gentle resistance is met. 0.5 mL/kg of 0.9\% NaCl is then instilled
through the catheter and aspirated into the same syringe. Most of the
cultures were collected while the patient was admitted for illness.
Routine surveillance cultures are not part of the standard of care at
our institution.

Outpatient treatment of respiratory tract infections involved increasing
frequency and/or intensity of routine AWC measures. Such measures
included chest physiotherapy via manual percussion or high-frequency
chest wall compression vests, cough assist and nebulized inhalation of
albuterol and 3\% sodium chloride. Treatment may also include enteral or
inhaled antibiotics in addition to increasing AWC, which are usually
selected based on patient symptoms and clinician judgement. We defined a
treatment episode as a recommendation to increase AWC and/or begin an
antibiotic in the outpatient setting (i.e. via phone or during a clinic
visit) for treatment of an LRTI. LRTI was physician defined and included
diagnoses of tracheitis, tracheobronchitis or pneumonia and/or symptoms
of cough, increased work of breathing, fever, or change in tracheostomy
secretions. Details of each treatment episode were recorded including
date of treatment, patient symptoms and whether increased AWC only or
antibiotics and increased AWC were recommended by the practitioner.
Additional treatment episodes within a 28 day period were not included
if the encounter resulted in the same intervention. Additional episodes
were included if the treatment method changed.

\emph{Statistical analysis}

Demographic and clinical characteristics were compared between the
treatment groups in a bivariate manner, using Wilcoxon rank-sum tests
for continuous variables, due to data skewness, and Chi-Square tests for
categorical data, using Fisher's Exact when expected cell counts were
small.

The primary outcome was hospitalization. If a hospitalization occurred
within 28 days of an outpatient treatment episode, it was counted as a
failure of that treatment. Generalized Estimating Equations (GEE) models
were used to determine the association between treatment (AWC alone
versus any antibiotics) and hospitalization. Unadjusted and adjusted
models were both performed, with the covariates in the multivariable
adjusted model being chosen based on their clinical relevance:
hospitalization within the past three months of a treatment episode, any
prior respiratory culture positive for \emph{Pseudomonas aeruginosa} ,
indication for tracheostomy (prematurity, neuromuscular disease and
airway obstruction) and time since tracheostomy placement.

All analytic assumptions were verified and analyses were performed using
SAS v9.4 (SAS Institute, Cary, NC). This study was approved by Indiana
University Institutional Review Board. All data was stored on a REDCap
database.

\emph{Results}

\emph{Patient and treatment characteristics}

Eighty- two patient charts were reviewed. Ten patients did not have any
treatment episodes and were not included in the study. Baseline
demographic and clinical characteristics are outlined in Table 1. There
were 355 treatment episodes amongst 72 patients over the 7 year study
period. The majority of patients were white and male. The most common
indications for tracheostomy were prematurity and neuromuscular disease.
Sixty-four of the 72 patients were ventilator dependent at some point
over the course of this study. Two patients died during the study period
with median age at death of 6 years.

Of the 355 treatment episodes, 160 (45\%) episodes involved increasing
AWC alone and 195 (55\%) were given an antibiotic in addition to
increasing AWC. Inhaled tobramycin was the most commonly prescribed
antibiotic, followed by amoxicillin-clavulanate (Table
2).\emph{Pseudomonas aeruginosa} was the most common species on
respiratory culture followed by S\emph{tenotrophomonas maltophilia} and
then methicillin resistant \emph{Staphylococcus aureus} (MRSA) (Table
3). Those who cultured \emph{P. aeruginosa} at any time were more likely
to be treated with inhaled tobramycin compared to other outpatient
antibiotics. Patients who never cultured \emph{P. aeruginosa} were often
treated with anti-pseudomonal therapy. Children who ever
cultured\emph{S. maltophilia} were often treated with antibiotics that
did not provide coverage.

\emph{Risk of hospitalization}

Of the 355 treatment episodes, 72 episodes represented retreatment with
the same treatment method within a 28 day period so these were not
included in the analysis. Of the 283 unique treatment episodes that
remained, 21.7\% of those who received increased frequency of AWC only
were hospitalized within 28 days of treatment, compared to 13.8\% that
were hospitalized after treatment with increased airway clearance and
oral/inhaled antibiotics, p= 0.08. The unadjusted odds ratio for
hospitalization was 1.73 (95\% CI: 0.88, 3.42); p=0.11, for treatment
episodes treated with AWC alone compared to treatment episodes treated
with AWC and antibiotics. In a multivariable model adjusting for
important clinical covariates, the odds of hospitalization remained
non-significant, adjusted OR 1.47 (95\% CI: 0.75, 2.86) (Table 4). Among
the selected covariates, hospitalization within the previous three
months of a sick call was associated with reduced odds of
rehospitalization.

\emph{Discussion}

There is substantial variability in the surveillance and management of
children with tracheostomy. Clinical guidelines are lacking in several
aspects of tracheostomy care, including outpatient management of
respiratory infections. Hospitalizations for these patients are lengthy,
costly and common. To our knowledge, this is the first study to describe
the outpatient treatment of respiratory infections, as well as to
examine the impact of hospitalizations on children with long term
tracheostomy.

In this study, we retrospectively analyzed whether hospitalization rates
due to LRTI in patients with tracheostomy were affected by outpatient
treatment methods of either receiving only increased AWC or receiving an
antibiotic in addition to increased AWC. We found that those who
received only AWC did not have significantly higher odds of
hospitalization within 28 days of treatment, compared to those who
received an antibiotic. This data indicates that there may be no
advantage to prescribing antibiotics. Antibiotics can be costly, can
induce bacterial resistance and can have systemic side effects, even in
the case of inhaled tobramycin as renal failure and ototoxicity have
been reported \textsuperscript{6-8}.

We identified no studies that evaluated the same interventions and
outcome. However a study by Zhu \textsuperscript{4} investigated
hospitalizations due to ambulatory care sensitive conditions (ACSCs)
which were defined as conditions for which good outpatient care could
potentially prevent the need for hospitalization or for which early
intervention could prevent complications. They found the most frequent
and costly ACSCs that lead to hospitalization were bacterial pneumonia
and tracheostomy infection. This study, along with our study where we
found that patients called frequently for respiratory concerns and were
treated often for these illnesses, indicates a need to identify optimal
treatments to effectively treat LRTIs at home.

As noted earlier in the study, inhaled tobramycin was the most commonly
prescribed antibiotic. Anecdotally, many parents prefer inhaled
tobramycin due to its localized activity and fewer systemic side effects
such as diarrhea and abdominal upset. In the absence of evidence based
guidelines for treatment of LRTI in this patient population, antibiotic
choice was determined by previous respiratory culture results,
patient/parent preference, accessibility to and availability of the
medication, insurance coverage and affordability. The intravenous form
of tobramycin for inhalation is not widely available in outpatient
pharmacies, with enteral antibiotics often being prescribed in its
place.

Despite minimal data, treatment of LRTI is often based on previous
cultures or most common bacteria cited in the literature (\emph{P.
aeruginosa} and MRSA)\textsuperscript{5}. In agreement with previous
studies, we found \emph{P. aeruginosa} to be the most commonly isolated
pathogen on respiratory cultures \textsuperscript{9,10}. This is in part
due to the tenacious nature of Pseudomonas which strongly adheres to the
tracheal mucosa \textsuperscript{9}. Though there is conflicting
evidence, several authors have shown MRSA to also be prevalent in
tracheal cultures, second to \emph{P. aeruginosa}\textsuperscript{9,10}.
Nevertheless this was not the case with our study where \emph{S.
maltophilia} was actually more common than MRSA.

The cystic fibrosis (CF) literature has demonstrated an association
between \emph{P. aeruginosa} acquisition and increased pulmonary
exacerbation rates, declining lung function and greater
mortality\textsuperscript{11-13}, as well as shortened survival in those
with MRSA \textsuperscript{14}. The acquisition and outcomes of
eradication of \emph{P. aeruginosa} and MRSA in pediatric patients with
tracheostomy remains unclear though a retrospective study by
Russell\textsuperscript{15} showed that acquisition of \emph{P.
aeruginosa} was associated with significantly increased odds of
readmission for respiratory tract infections within 12 months of
discharge from the tracheostomy placement hospitalization.

While obtaining routine respiratory cultures is the norm in patients
with cystic fibrosis\textsuperscript{16,17}, there is no evidence
showing the benefit of collecting surveillance respiratory cultures in
healthy patients with tracheostomy. Biofilm is known to develop in
tracheostomy tubes as soon as 7 days after tracheostomy tube change or
initial placement \textsuperscript{18} and results in subsequent
bacterial colonization of the airway. Cline et
al\textsuperscript{19}showed that bacteria and antibiotic sensitivity
can change between consecutive respiratory cultures and thus use of
prior cultures was of limited benefit for choosing antibiotic therapy in
treating exacerbations. In addition, reports have shown that
colonization without infection is common and there are no good methods
for distinguishing colonization (which may not require treatment) from
overt infection that requires intervention \textsuperscript{20,21}.

Nevertheless, many practitioners use prior respiratory cultures as a
guide for treatment of LRTI\textsuperscript{5}. However, despite the
prevalence of \emph{S. maltophilia} in our patients' respiratory
cultures, trimethoprim-sulfamethoxazole was not prescribed as often as
would be expected. This could be because \emph{S. maltophilia} may not
have grown on the most recent culture and so was not thought to be the
cause of the current LRTI. We also think it could be due to previous
findings showing that most children with tracheosomy will
acquire\emph{P. aeruginosa\textsuperscript{10,15}} and would benefit
from anti-pseudomonal targeted therapy. A recent study
\textsuperscript{22}evaluated treatment of \emph{S. maltophilia} in
children with tracheostomy and acute respiratory illness. They found no
difference in the amount of time to return to respiratory baseline after
treatment targeting \emph{S. maltophilia} with
trimethoprim-sulfamethoxazole versus those who were also \emph{S.
maltophilia} positive but did not receive targeted treatment. This study
shows there may be no benefit of targeted treatment of \emph{S.
maltophilia} in this group, but more rigorous evaluation is needed.

There were several limitations to this study. This is a retrospective
study, so we cannot ascribe causality to interventions for LRTI. Our
sample size was small and does not preclude type II error, i.e., that
antibiotics are effective in reducing LRTI hospitalizations in children
with tracheostomy. Additionally, most of the patients were young and
received a tracheostomy for prematurity and neuromuscular disease.
Further study is required for children over 6 years of age as well as
patients with other indications for tracheostomy.

We accounted for four confounders that we thought most impacted outcomes
including lower odds of hospitalization if patients were recently
hospitalized; however there were other confounders that we did not
evaluate such as socioeconomic status, smoke exposure at home, daycare
or school attendance and home nursing since this data was missing or
incomplete. Cristea et al \textsuperscript{23} showed that chronically
ventilated children who lived in lower ZIP code- based annual household
income areas had higher mortality.

Next, several patients also received treatment outside of Riley Hospital
(such as antibiotics for LRTI from primary care provider) and we were
only aware of these treatment episodes if parents called our clinic to
report it. Our study was focused on chronically ventilated patients as
these patients were more likely to be treated solely within our hospital
system compared to patients who were not chronically ventilated,
ensuring that we were less likely to miss any episodes of LRTI. It is
reasonable to assume that we underestimated the number of treatment
episodes given outside of Riley Hospital considering it was easier to
see the local pediatrician than our outpatient clinic for a sick visit
either due to distance or sick visit availability. Similarly, patients
were sometimes hospitalized outside of Riley Hospital. We were only
aware of the hospitalizations if discharge paperwork was sent to us and
so the number of hospitalizations was also likely underestimated. Our
analysis does not account for adherence to the prescribed treatments.
Diagnosis of LRTI lacks consistency owing to various definitions of
infection and treatment recommendations, further complicating decision
to treat with antibiotics \textsuperscript{24,25}.

\emph{Conclusions}

Children with tracheostomy represent a vulnerable population of patients
who often have multiple complex co-morbidities and have high level of
resource utilization and antibiotic exposure. Our study shows that these
children are frequently treated for respiratory illness. Successfully
treating illnesses at home would minimize healthcare costs and avoid
hospitalizations. We did not find a difference in subsequent 28 day
hospitalization between starting outpatient antibiotics versus only
increasing AWC, indicating that antibiotics may not help with avoiding
hospitalization and should be used only after careful consideration of
the patient's clinical status and medical history. Prospective studies
to determine optimal outpatient treatment strategies are needed.

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