Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Tumor Lysis Syndrome: A Systematic Review of

Case Series and Case Reports

Belal M. Firwana MD, Rim Hasan MD, Nour Hasan MD, Fares Alahdab MD,
Iyad Alnahhas MD, Seba Hasan MD & Joseph Varon MD, FACP, FCCP, FCCM

To cite this article: Belal M. Firwana MD, Rim Hasan MD, Nour Hasan MD, Fares Alahdab MD,
Iyad Alnahhas MD, Seba Hasan MD & Joseph Varon MD, FACP, FCCP, FCCM (2012) Tumor Lysis
Syndrome: A Systematic Review of Case Series and Case Reports, Postgraduate Medicine,
124:2, 92-101, DOI: 10.3810/pgm.2012.03.2540

To link to this article: http://dx.doi.org/10.3810/pgm.2012.03.2540

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Tumor Lysis Syndrome: A Systematic Review
of Case Series and Case Reports
Belal M. Firwana, MD 1
Rim Hasan, MD 1
Nour Hasan, MD 2
Fares Alahdab, MD 2
Iyad Alnahhas, MD 2
Seba Hasan, MD 2
Joseph Varon, MD, FACP,
FCCP, FCCM 3
1
Department of Internal Medicine,
University of Missouri, Columbia,
MO; 2University of Damascus, Faculty
of Medicine, Damascus, Syria; 3The
University of Texas Health Science
Center at Houston, Houston, TX
Correspondence: Joseph Varon, MD, FACP,
FCCP, FCCM,
The University of Texas Health Science
Center at Houston,
The University of Texas Medical Branch
at Galveston,
2219 Dorrington St.,
Houston, TX 77030.
Tel: 713-669-1670
E-mail: jvaron@roamer.net
92 Postgraduate Medicine, Volume 124, Issue 2, March 2012, ISSN 0032-5481, e-ISSN 1941-9260
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C L I N I C A L F E AT U R E S
DOI: 10.3810/pgm.2012.03.2540
Abstract: Tumor lysis syndrome (TLS) is a clinical condition that is caused by a massive
lysis of tumor cells that accumulate very rapidly and disturb hemodynamics. This oncologic
emergency requires immediate intervention. Tumor lysis syndrome was first described in the
19th century. Since then, it has become a well-known disease with improved management
measures. Tumor lysis syndrome can occur after any type of neoplasm. It is highly associated
with rapidly proliferating tumors compared with those that are well demarcated, such as acute
lymphoblastic leukemia and high-grade non-Hodgkin lymphoma. Initiation of chemotherapy,
radiotherapy, or steroid treatment may trigger TLS, or it may develop spontaneously. The
release of massive quantities of intracellular contents may produce hyperkalemia, hyper-
phosphatemia, secondary hypocalcemia, hyperuricemia, and acute renal failure. Prevention
and treatment measures include intravenous hydration, use of allopurinol and rasburicase,
management of TLS-associated electrolyte abnormalities, and renal replacement therapy; the
use of urine alkalinization remains controversial. In this article, we summarize the findings
of case series and case reports published over the past 6 years in an effort to help familiarize
clinicians better recognize and manage TLS.
Keywords: tumor lysis syndrome; neoplasm; kidney failure; rasburicase; allopurinol; uric acid;
hyperphosphatemia; hyperkalemia
Introduction
Tumor lysis syndrome (TLS) is an oncologic emergency that requires immediate
interventional action.1 It is caused by a massive lysis of tumor cells that accumulate very
rapidly, or, more commonly, by the destruction of tumor cells by cytotoxic agents.24
Tumor lysis syndrome is considered an emergency because it disturbs hemodynamics.
Because a large amount of cells are being destroyed, massive amounts of potassium,
phosphate, and uric acid are released from these cells.5 Uric acid accumulates and
precipitates in the kidney tubules, leading to acute kidney injury.6 The increase in
serum phosphate and calcium phosphate lead to deposition of these salts in the tubules,
leading to renal failure.7
Being a critical and emergent syndrome, many physicians try to avoid TLS through
several preventive measures. Many studies have addressed various ways to prevent
and manage TLS, which basically affect the kidney to prevent disposition of salts in
its tubules, thus preventing the occurrence of renal failure.8 Some of these measures
include aggressive intravenous hydration, urine alkalinization, or agents that decrease
the concentration of uric acid in the serum in order to decrease its deposition in renal
tubules, such as allopurinol and rasburicase.3
 Tumor Lysis Syndrome

Methodology Results
The primary aim of this systematic review was to Description of Patients and Neoplasms
describe cumulative TLS presentations of individual A total of 91individual case reports or case series were
patients in case reports and case series, their underlying identified from the search, from which a total of 105 patients
neoplasms, TLS development triggers, and treatment with different neoplasms were reported.998 Of these, 73
modalities used. Because there are not many random- (70%) were men (mean age, 4922 years) and 30 (29%)
ized clinical trials addressing these aspects, this article were women (mean age, 4123 years). Among patients
summarizes the etiologies, presentations, treatments, who presented with a primary neoplasm and developed TLS,
and outcomes that have been reported in previously hematologic malignancies accounted for 62% of those neo-
published case series and individual case reports on TLS. plasms, while solid tumors accounted only for 38% (Table1).
This information is presented in order to enhance and
encourage further clinical trials, which could eventually Hematologic Malignancies
lead to better evidence-based management. Among hematologic malignancies, the most common malig-
nancy was leukemia (30%). Acute lymphocytic leukemia
Information Sources and Search Methods was the most frequent presentation (42%), followed by
A comprehensive literature search was conducted using chronic myelogenous leukemia (29%), acute myelogenous
the Medline database for abstracts using various com- leukemia (19%), and chronic lymphocytic leukemia (10%).
binations of the terms tumor, lysis, and chemo- Non-Hodgkin lymphoma represented 25% of hematologic
therapy in the abstract or title. Two authors identified malignancies, of which B-cell lymphoma constituted of 88%.
articles eligible for further review by screening abstracts Only 1 (1%) patient had mycosis fungoides, a cutaneous
and titles. If a study was deemed relevant, the article
Table 1. Type of Neoplasms Preceding TLS
was obtained and reviewed. In addition, bibliographic
Neoplasm Preceding TLS N %
references of identified articles were reviewed to find
Hematologic malignancies
case reports and series not identified by the electronic
Leukemia 31 29.5
searches.
ALL 13 12.4
AML 6 5.7
Study Identification CLL 3 2.9
The data sources were searched for possible studies CML 9 8.6
Non-Hodgkin lymphoma 25 24.8
limited to publication dates between September 2004
B-cell lymphoma 22 21.0
and September 2010. The search was limited to English- T-cell lymphoma 4 3.8
language articles. Individual case reports or case series Multiple myeloma 7 6.7
involving patients who had similar conditions were Hodgkin lymphoma 1 1.0
articles of interest, regardless of treatment or disease Solid tumors
course. The final search identified 91 original articles Gastrointestinal cancers 13 12.4
that fulfilled the inclusion criteria. Hepatocellular 8 7.6
Other gastrointestinal 5 4.8
Lung cancers 5 4.8
Data Collection and Extraction Castleman disease 4 3.8
The prespecified data elements were extracted from each Melanoma 3 2.9
trial, including patient demographics and baseline char- Ovarian 3 2.9
acteristics, type of underlying neoplasm, the cause/trig- Others 11 10.5
Neuroblastoma 2 1.9
ger of TLS development, and what treatments were used.
Prostatic 2 1.9
Kidney 2 1.9
Statistical Analysis Breast 1 1.0
From the abstracted data, we calculated numbers and per- Testicular 1 1.0
centages for dichotomous data and means and standard Thymoma 1 1.0
Uterine 1 1.0
deviations for continuous data. We used SPSS statistical
Pelvic 1 1.0
software (SPSS version 17.0) for data management and
Abbreviations: ALL, acute lymphocytic leukemia; CML, chronic myelogenous
statistical analysis. leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia;
TLS, tumor lysis syndrome.

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Firwana etal

T-cell lymphoma. Burkitts lymphoma occurred in 5 patients, Table 2. TLS Triggering Factors
7 patients presented with multiple myelomas, and 1 patient TLS Triggers
developed TLS after having a Hodgkin-type lymphoma (1%) Chemotherapy
(Table1). Spontaneous
Glucocorticoids
Radiotherapy
Solid Tumors Others
Among solid tumors, different gastrointestinal cancers were Anesthesia-induced
the most common presentation (12.5%), either hepatocel- After treatment of pneumonia
lular carcinomas (8%) or other gastrointestinal neoplasms After splenic artery embolization
After staging laparotomy
(5%), followed by lung cancers (5%), Castleman disease
After a surgery (not specified)
(4%), melanoma (3%), and ovarian cancer (3%). Three of After dose reduction of
the gastrointestinal tumors were colorectal cancers, 1 was immunosuppression
a stomach neuroendocrine carcinoma, and 1 was a gastro- Abbreviation: TLS, tumor lysis syndrome.
N %
60 57.1
27 25.7
7 6.7
3 2.9
7 6.7
2 1.9
1 1.0
1 1.0
1 1.0
1 1.0
1 1.0

intestinal stromal tumor. Two cases of lung cancer were

adenocarcinomas, 1 was a small cell lung cancer, and 1 was
a stage IV squamous cell carcinoma of the lung (Table1).
The rest of the cases were neuroblastoma (2%), prostatic
carcinoma (2%), breast cancer (2%), kidney neoplasms
(2%), testicular seminoma (1%), thymoma (1%), stage
IV endometrial cancer, and pelvic neuroectodermal
tumor (1%).
TLS Development
Although almost all patients who developed TLS
presented with a neoplasm prior to its develop-
ment, TLS can be triggered by different factors,
or can occur spontaneously. Most patients devel-
oped TLS after the initiation of a treatment, either
with chemotherapy, glucocorticoid, or radiotherapy.
In most cases, TLS was triggered after initiation of
chemotherapy for treatment of an existing neoplasm
(57%); these chemotherapies vary in their mechanisms
of action and in the target organelles that they affect.
Seven percent of the cases were triggered by the initia-
tion of glucocorticoid treatment and 3% occurred after
radiotherapy. Interestingly, 26% of cases developed
TLS spontaneously, without use of any chemotherapy,
radiotherapy, or steroid therapy (Table2).
The rest of the cohort had unusual presentations of TLS.
Two patients developed TLS after initiation of anesthesia,
1 patient after pneumonia treatment with an anti-
biotic, 1 patient after splenic ar ter y emboliza -
tion, and 2 patients after surgical procedures. The
f irst patient who developed TLS after surgery had
a staging laparotomy, and the other patient was on immu-
nosuppression therapy with azathioprine and tacrolimus
prior to surgery, but developed TLS after reducing dos-
Treatment Modalities Used for TLS
A variety of treatment modalities are reported for treating
TLS. Allopurinol was used in 54% of patients, rasburicase
and uric oxidase were used in 35% of patients, urine alkali-
zation agents were used in 36% of patients, hydration with
intravenous fluids was used in 37% of patients, and renal
replacement therapy, including both hemodialysis and peri-
toneal dialysis, was used in 40% of patients (Table3).
Some reports described other modalities for treating TLS
and its complications, such as loop diuretics for increased
levels of electrolytes, which were used in 11% of patients.
Many patients were placed on mechanical ventilatory, car-
diopulmonary, and inotropic support. Some patients were
given calcium carbonate, glucose plus insulin, and sodium
polystyrene sulfonate for hyperkalemia, and aluminum
hydroxide for hyperphosphatemia and hydroxyurea. Some
patients had their blood products replaced with fresh frozen
plasma, and others underwent autologous peripheral blood
progenitor cell transplantation.
Discussion and Literature Review
History
Tumor lysis syndrome was first introduced in the medical
literature during the early 20th century. In 1929, Bedrna and
Polck99 described the effect of x-ray irradiation treatment
Table 3. TLS Treatment Modalitiesa
TLS Triggers N %
Hydration and IV fluids 61 58.1
Allopurinol 57 54.3
Urate oxidase (ie, rasburicase) 37 35.2
Alkalization of urine 38 36.2
Renal replacement therapy 42 40.0
Each case may be treated with 1 treatment modality; cumulative percentage does
a

ages of these regimens (Table2). not equal 100%.

Abbreviation: IV, intravenous; TLS, tumor lysis syndrome.

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on patients with chronic leukemia, and how they devel-
oped hyperuricemia and acute kidney failure afterward.
Years later, Merrill100 reported the occurrence of hyperuri-
cemia following irradiation therapy. Merrill100 noted that
from 1927 to 1939, among 12 patients who died of
hematologic malignancies, 3 patients died shortly after
the administration of x-ray therapy and had uremia. Prior
to these reports in the 19th century, hyperuricemia and
hyperuricosuria were described in patients with leukemia.
As early as 1851, hyperuricemia and uricosuria were noted
as complications of leukemia by Rudolph Virchow.101 In
1870, Salkowski102 described a patient with splenic leu-
kemia who had increased uric acid output in the urine.
Currently, TLS is a known consequence of various tumors
after their treatment with chemotherapy and radiotherapy.
Crush injury syndrome and rhabdomyolysis share the same
pathophysiology of cell body injury and substance release
as TLS. These conditions started to be described in the
literature more frequently after World Wars I and II.103
Epidemiology and Etiology
Tumor lysis syndrome is observed after different types
of cancers, regardless of whether patients are treated
with chemotherapy or radiotherapy. The incidence of
TLS among patients undergoing remission-induction
chemotherapy is 10%. 104 Tumor lysis syndrome is highly
associated with rapidly proliferating tumors compared
with those that are well demarcated. 105 Both acute
lymphoblastic leukemia (ALL) and high-grade non-
Hodgkin lymphoma, particularly Burkitts lymphoma,
are the most commonly associated with TLS among rap-
idly proliferative tumors. 72,106108 According to Coiff ier
etal, 4 the occurrence of TLS in patients with ALL and
non-Hodgkin lymphoma is 47% and 22%, respectively.
Acute myelogenous leukemia is reported to develop
TLS less frequently than other neoplasms, 104,109,110
although in a large series of patients, 17% of patients
with AML developed TLS. 111 The mortality rate related
to TLS complications has been reported to be as high as
1.9% in patients with acute leukemia and non-Hodgkin
lymphoma. 112
Although solid tumors show a high percentage
among tumor incidences, TLS occurrence associated
with these tumors is somewhat rare. 113,114 Tumor lysis
syndrome can occur after small cell carcinoma of the
lung, breast carcinoma, germ-cell tumors, thymoma,
and hepatoblastoma.98,115,116 The mortality rate of patients
with TLS reported in solid tumors is high, at 35%. 113
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Tumor Lysis Syndrome
The different incidences of TLS in hematological and
solid tumors are mainly due to the differences in sensi-
tivities to anti-neoplastic treatment, as solid tumors do
not respond to those treatments as effectively as hema-
tologic tumors.114
Pathophysiology
In the presence of a tumor in the body with a high prolifera-
tive rate and/or a high sensitivity to treatment,117 initiation of
cytotoxic chemotherapy,74,111,118 steroid therapy,119 or radia-
tion therapy73,120 can result in TLS.121 Tumor lysis syndrome
can also occur spontaneously.14,122,123 This releases massive
quantities of intracellular contents, including potassium,
phosphate, and nucleic acids, which can be metabolized
to uric acid into the systemic circulation. The metabolic
consequences include hyperkalemia, hyperphosphatemia,
secondary hypocalcemia, and hyperuricemia (Figure1).124126
Nucleic acid is converted to hypoxanthine and xanthine,
respectively, by the enzyme xanthine oxidase. Hypoxanthine
and xanthine are then converted to uric acid, which accumu-
lates in the renal tubules and results in damage to the kidney
and acute renal failure.127 An increase in blood phosphorus
will lead to a decrease in blood calcium by binding each other.
Phosphorus and calcium are deposited into renal tubules and
cause renal failure, as uric acid does, and as a compound, they
affect heart automaticity by causing cardiac arrhythmias.128
Hyperkalemia will result in several consequences, including
abnormal heart rhythm and bradydysrhythmia with peaked T
waves,129 cardiac arrest,130 and generalized muscle weakness
(Figure1).131,132
Prevention and Treatment
Patients at risk for developing TLS should have their risk
stratified as low, intermediate, or high so that they may
undergo the appropriate prevention and treatment modali-
ties. A model for TLS risk classification has been recently
proposed by an expert TLS panel consensus.133,134 Risk strat-
ification is based on a 3-step risk attribution that considers:
1) laboratory-confirmed TLS (increased uric acid, potas-
sium, or phosphate), 2) disease type (hematological vs
solid neoplasms), and 3) renal function/involvement. 133,134
The cornerstone of TLS management is using preventive
measures. Measures used for the prevention and treat-
ment of TLS include intravenous hydration, urine
alkalinization, use of hypouricemic agents, both allopu-
rinol and rasburicase, management of TLS-associated
electrolyte abnormalities, and, in select cases, renal
replacement therapy.105,135,136
Firwana etal
Figure 1. Pathophysiology of tumor lysis syndrome.
Hypersensitive
Neoplastic cells
Chemotherapy
Antibodies
CH3
H H
Normal cells HO
H
Steroids
K
Na +
Extracellular space
Myocyte
K +
Peaked T waves
Muscle weakness
Intravenous Hydration
Aggressive intravenous hydration is the cornerstone of pre-
venting TLS. It works by increasing intravascular volume
and thus decreasing serum solute concentration, enhancing
renal blood flow, glomerular filtration rate, and urine vol-
ume.137,138 This mechanism decreases the concentration of
uric acid in renal tubules, making the precipitation of uric
acid less likely.8 The International Expert Panel guidelines
published in 2010 recommended that patients with TLS
receive intravenous fluid initially at the rate of 2 to 3L/m2
per day. Urine output should be maintained within a range
of 80 to 100mL/m2 per hour.134
Urinary Alkalinization
The role of urinary alkalinization in TLS remains contro-
versial. Use of either acetazolamideand/or sodium bicar-
bonateto alkalinize the urine has the potential benefit of
converting uric acid to the more soluble urate salt, thereby
promoting the urinary excretion of urate and diminishing
the likelihood of uric acid precipitation in the tubules.4,139
Disadvantages of urine alkalinization include promotion
of calcium phosphate deposition in the kidney, heart, and
other organs in patients with hyperphosphatemia.140 Another
drawback to systemic alkalinization is that it exacerbates
hypocalcemia by shifting ionized calcium to its nonionized
96 Postgraduate Medicine, Volume 124, Issue 2, March 2012, ISSN 0032-5481, e-ISSN 1941-9260
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Potassium
Phosphorus
Nucleic acids
Radiation
CH2 O
H
K
P
Ca
Ca-P
XO
Dysrhythmia Uric acid
Acute renal
failure
form.118 In addition, the only available experimental study
using a rat model concluded that hydration with saline alone
is as effective as alkalinization in the prevention of uric acid
precipitation.141 For these reasons, urinary alkalinization
is no longer routinely used. The 2010 International Expert
Panel guidelines recommended that the use of sodium bicar-
bonate only be indicated in patients with severe metabolic
acidosis.134 Some data suggested that urine alkalinization
has effectiveness similar to that of intravenous hydration
in minimizing uric acid precipitation, and plays a minor
preventive role.141
Allopurinol
Allopurinol is a purine that competitively inhibits
xanthine oxidase, which catalyzes the conversion of
xanthine and hypoxanthine to uric acid. Inhibition of
xanthine oxidase eventually leads to a decrease in uric
acid formation and thus a decrease in blood and urine
urate levels, preventing uric acid crystals from precipi-
tating in renal tubules, which in turn protects the kidney
from obstructive uropathy, which is usually associ-
ated with TLS in malignant disease. 135,138 The problem
with allopurinol use is that it increases serum levels of
xanthine, which may lead to xanthinuria, and therefore
bears the risk of xanthine nephropathy or xanthine stone

formation. 85,142145 Allopurinol should be initiated in
patients with intermediate risk for TLS (100300mg
orally every 8 hours) in addition to hydration and
continuous monitoring for TLS and TLS complica-
tions. Allopurinol may be considered prior to induction
of chemotherapy and can be administered orally or
intravenously.4,134,135,146
Rasburicase
Rasburicase is a urate oxidase that converts uric acid to
allantoin, which is 5 to 10 times more soluble in urine
than uric acid, and therefore causes a rapid reduction
in uric acid levels.147 For this reason, it is effective in
preventing and treating hyperuricemia and TLS.135,148152
Randomized controlled trials conducted on pediatric
patients showed that different doses of rasburicase were
effective and well tolerated for the management of hyper-
uricemia, and when compared with allopurinol, were
more effective and had an earlier onset of action. 135,152
A recent systematic review showed that although urate
oxidase might be effective in reducing serum uric acid, it
is still unclear whether this translates into a reduction in
mortality or renal failure.153 Rasburicase is recommended
to be initiated in adult and pediatric patients who are at
high risk for TLS, starting with 1 dose (0.10.2mg/kg) and
repeating the dose if necessary, in addition to hydration and
close monitoring. Rasburicase has been shown to decrease
levels of plasma uric acid more rapidly in patients at high
risk for TLS compared with allopurinol.4,134,135
Renal Replacement Therapy
Renal replacement therapy (eg, hemodialysis, peritoneal
dialysis, and continuous arterial-venous hemodialysis)
has been used as the last treatment option in some cases
to maintain normal kidney function, correct electrolyte
abnormalities, and improve patient outcomes. 105,154
In an oncologic pediatric population, 21% of children
with advanced Burkitts lymphoma required hemodialy-
sis during induction chemotherapy, despite being treated
with allopurinol, hydration, and urinary alkalinization. 155
When dialysis is initiated early, serum uric acid and
phosphate concentrations will decrease rapidly, and it
will lead to a complete recovery of renal function.156
Diminished urine flow responds quickly to hemodialysis,
as it is efficient in removing uric acid; serum uric acid
levels decrease by about 50% with each 6-hour treat-
ment. 156 The 2011guidelines for the management of
TLS recommend renal replacement therapy whenever
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Tumor Lysis Syndrome
treatment fails for hyperphosphatemia, hyperkalemia,
uremia, or renal dysfunction.4 Early initiation of dialysis
improves prognosis.133
Conclusion
Tumor lysis syndrome is an oncologic emergency that
requires early detection and needs immediate interven-
tional action. It is a condition caused by a massive lysis
of the tumor cells accumulating very rapidly, or by
destruction of tumor cells by cytotoxic agents. It disturbs
hemodynamics by releasing cell contents into the plasma
current. The aim of this article is to help clinicians to
better recognize and manage TLS.
Tumor lysis syndrome is observed most frequently
in patients with rapidly proliferating tumors, such
as ALL and high-g rade non-Hodgkin lymphoma,
particularly Burkitts lymphoma. Tumor lysis syn-
drome may occur spontaneously, or may follow
the initiation of treatment with chemotherapy or
radiation therapy. The best modality used for prophy-
laxis of TLS is aggressive intravenous hydration. It
decreases the concentration of uric acid in the urine,
and though, precipitation of uric acid becomes less
likely to occur in renal tubules. Aggressive intrave-
nous hydration is recommended for all patients at
high or intermediate risk for TLS. As allopurinol, a
xanthine oxidase inhibitor, prevents the formation of
uric acid, it prevents urate crystals from precipitating.
Allopurinol is recommended for the initial manage-
ment in patients at intermediate risk for TLS, rather
than rasburicase, if uric acid levels are not elevated
prior to the treatment. On the other hand, rasburicase,
a urate oxidase, makes uric acid more soluble in urine
and causes a rapid reduction in uric acid levels. Rasbu-
ricase is recommended for the initial management of
patients at high risk for TLS, rather than allopurinol.
Renal replacement therapy is used as a last resort to
improve kidney function and persistent electrolyte
abnormalities. Early initiation of renal replacement
therapy improves prognosis. Urinary alkalinization use
is still controversial and is only indicated in patients
with severe metabolic acidosis.
Acknowledgments
The authors thank Mazen Ferwana, MD, PhD, ABFM,
JBFM, from King Saud bin Abdualziz University for
Health Sciences, Riyadh, Kingdom of Saudi Arabia,
for help with outlining and designing the article.
Firwana etal
Conflict of Interest Statement
Belal M. Firwana, MD, Rim Hasan, MD, Nour Hasan, MD,
Fares Alahdab, MD, Iyad Alnahhas, MD, Seba Hasan, MD,
and Joseph Varon, MD, FACP, FCCP, FCCM disclose no
conflicts of interest.
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