Introduction
Pyrexia of unknown origin (PUO) was defined in 1961 by Petersdorf and Beeson as (1)
a temperature greater than 38.3° C (101° F) on several occasions, (2) more than 3
weeks’ duration of illness, and (3) failure to reach a diagnosis despite 1 week of
inpatient investigation [1]
[2]. Patients with cirrhosis and PUO offer several challenges with regard to management;
obtaining a tissue diagnosis is difficult due to coagulopathy and collaterals. Differential
diagnosis of PUO is very broad and often these patients are started on empirical anti-tubercular
treatment (ATT) [3]. Tuberculosis is a common cause of PUO. Extrapulmonary tuberculosis is more common
than pulmonary tuberculosis in patients with cirrhosis, thus patients present without
pulmonary infiltrates and tissue diagnosis is required [4]. Empirical ATT has a risk of hepatotoxicity and this risk is higher in patients
with cirrhosis and may cause further decompensation of liver disease or acute-on chronic
liver failure that is associated with high mortality [5]
[6]
[7]. Thus, it is not recommended to start empirical ATT. There is also a risk of exacerbation
of tuberculosis after initiation of immunosuppressant treatment in liver transplant
recipients, thus pretransplant diagnosis and treatment are necessary. The practice
of empirical ATT is common in tropical countries such as India due to the high prevalence
of tuberculosis. Excision biopsy from abdominal lymph nodes carries a high risk in
patients with cirrhosis, and patients with Child Pugh class C are very poor candidates
for such sampling (even laparoscopic) [8]. Empirical ATT may also delay the true diagnosis and thus may worsen the original
disease. EUS guided FNA offers several advantages: it can be performed with conscious
sedation, the FNA procedure is real time, vision guided, and vascular structures (or
collaterals) can be safely avoided.
There are no literature reports with regard to EUS-FNA in these patients. A case report
of cirrhosis with pyrexia of unknown origin which proved to be histoplasmosis on EUS-FNA
was published by our institute [9]. The aim of this current study was to examine the safety and impact of EUS guided
FNA in patients with cirrhosis.
Methods
The study was conducted prospectively between January 2014 and January 2016 at a tertiary
care center in North India (Delhi NCR). Out of 6104 patients with cirrhosis, 70 patients
had PUO as shown in [Table 1]. Sixteen patients with PUO were in the ICU and were very critical, hence FNA was
not done. Four patients did not give consent for the FNA procedure. In eight patients,
lymph nodes were considered to be accessible by transabdominal ultrasound; four of
these patients were referred for EUS guided FNA later due to intervening collaterals.
Thus, 46 patients with cirrhosis and PUO with lymphadenopathy or adrenal enlargement
on imaging who underwent EUS guided FNA, were included in the analysis ([Table 1]). The study had approval from the institute’s review board/ethics committee. The
standard definition for PUO was used [2].
Table 1
Break-up of PUO in patients with liver cirrhosis and accessibility of lymphadenopathy.
|
Total number of CLD patients screened in OPD/IPD
|
6104
|
|
CLD with PUO and lymphadenopathy
|
70
|
|
Not assessed for FNA (very sick/no consent)
|
20 (16/4)
|
|
Considered to be accessible for transabdominal ultrasound
|
8
FNA done in 4, not done in 4 due to intervening collaterals (EUS done in these 4 patients)
|
|
EUS guided FNA performed
|
46 (including 4 referred from transabdominal ultrasound)
|
CLD, chronic liver disease; EUS, endoscopic ultrasound; FNA, fine needle aspiration;
IPD, inpatient department; OPD, outpatient department; PUO, pyrexia of unknown origin.
Three patients had cirrhosis with PUO and enlarged adrenals for which EUS FNA was
done. All of the procedures were carried out under conscious sedation (Midazolam).
EUS guided FNA was performed using a GF-UCT140 linear echo-endoscope (EUS scope, Olympus,
Tokyo, Japan). Work-up for pyrexia included ascitic fluid analysis, urine culture,
blood culture, malaria serology, chest X-ray, and contrast enhanced CT of the abdomen
and thorax. Patients who had enlarged lymph nodes or adrenal/adrenals underwent EUS
guided FNA. The following data were recorded for each patient: age, sex, site of lymph
node, size of lymph node on its short and long axis, type and number of needle passes,
number of slides, results of FNA, and complications from the procedure. In the presence
of multiple lymph nodes, the node with larger size/with demarcated borders/hypoechoic
in nature was preferred for FNA. A lymph node was considered reactive when FNA showed
lymphoid cells in different stages of activation in the presence of adequate cellularity
and the absence of granulomas/necrosis/malignant cells. We aimed to follow-up all
these patients up to 6 months after the procedure.
EUS FNA procedure
A lymph node was selected based on the above mentioned criteria for FNA, if feasible
(avoidance of vascular structures and vital organs). A linear array echo-endoscope
was directly inserted into the esophagus. An EUS FNA needle with stylet was introduced
into the working channel; Doppler was used to avoid any vascular structures in the
needle path. The stylet was withdrawn slightly before puncture; it was reintroduced
fully after puncture of the lymph node to displace any material in the needle (from
the gastrointestinal wall). After that, the stylet was completely withdrawn; 10 – 20
to and fro movements of the needle were performed within the lymph node. The material
inside the needle was gradually pushed onto slides with the help of the stylet. Two
slides from each pass were immediately fixed in absolute alcohol and the remainder
were air dried. The slides were stained with Papanicolaou, Giemsa stain and Ziehl-Neelsen
stain (wherever required). The type of needle, method of FNA (suction, no suction
or capillary), and number of needle passes (as no on-site cytopathologist facility
was present) were operator-dependent. We used a 25G needle in the majority of the
patients. The average number of passes was 3 (2 – 5). Patients received a platelet
transfusion if the platelet count was < 50 000/cmm or fresh frozen plasma transfusion
if INR > 1.5. The patients were kept under observation for 6 hours in our dedicated
endoscopy post-procedure area adjacent to the endoscopic suite. They were observed
for vital examination, and immediate procedure or anesthesia related complications.
The patients were followed up by phone or outpatient department (OPD) basis for 1
week for any complications including bleeding, infection, and fever. Further follow-up
for 6 months was carried out to assess the clinical response to treatment.
Statistical methods
The data are shown as number, percentage, and median (25 – 75 IQR). Two groups were
compared with Student’s t test or Fishers exact test (nominal data). A two-tailed P value < 0.05 was considered to be significant. All statistical analyses were performed
with SPSS, version 16 (SPSS Inc., Chicago, Illinois, United States).
Results
The study group comprised 46 patients (40 males). A total of 50 FNAs were done (47
lymph nodes and three adrenals). The parameters of liver disease severity were as
follows: mean Child-Turcotte-Pugh (CTP) score 10 (8 – 11), mean Model for End-Stage
Liver Disease (MELD) score 18 (12 – 20). The Child Pugh class was A in 4, B in 14,
and C in 28 (including three patients with adrenal FNA). A total of 34 (73.9 %) patients
had ascites, platelet count was 1.2 × 105 (0.7 – 1.45 L)/cmm, and INR was 1.5 (1.17 – 1.65, maximum 3). The site of the sampled
lymph node was mediastinal in 10 and abdominal in 37 patients; adrenal FNA was taken
from the left adrenal in two patients with bilateral enlargement and the right adrenal
(isolated right adrenal enlargement) in one patient. Six patients required a platelet
transfusion; fresh frozen plasma was required in 22 patients before the EUS-FNA procedure.
One of these patients also had renal failure (serum creatinine 7.4 mg/dL). After the
EUS-FNA procedure, blood smearing of mucosa was seen in 18 patients (all abdominal
lymph nodes); none of the patients had clinically significant bleeding/melena. A 25G
FNA needle was used in the majority of patients (n = 26, all patients with Child’s
C), a 22 G needle was used in 17, and 19 G was used in one patient who had a calcified
lymph nodal mass and in whom the 22 G needle had failed to yield an aspirate. The
average number of passes was 3 (2 – 5).
Cytopathological diagnoses were metastatic carcinoma in one (right adrenal), granulomatous
change in 10 (six acid fast bacilli stain positive), histoplasmosis in three (two
adrenals), and reactive changes in 32. One patient had a pre-liver transplant diagnosis
of multiple small hepatocellular carcinomas and had pyrexia of unknown origin; his
abdominal lymph node showed the presence of granulomas without necrosis or positive
staining for tubercular bacilli. He was given anti-tubercular treatment which led
to improvement in his condition. Liver transplantation was done after a few weeks
and his explanted liver also showed the presence of granulomas. A total of 32 patients
had a diagnosis of reactive lymph node. These patients were followed for a period
of 6 months (4 patients for 3 months) and all had a benign course. Ten of these patients
had a liver transplant and had a benign course (one died after 3 months due to intracranial
bleeding). Four patients provided inadequate samples; one of these underwent biopsy
of the inguinal node which was positive for lymphoma. When pathologically enlarged
lymph nodes were compared to reactive lymph nodes, pathological nodes were larger
along the small and large axes; however, none of these parameters reached statistical
significance. Pathological lymph nodes tended to be less oblong and had a significantly
higher proportion with hypoechoic echotexture and sharply defined borders. One of
the lymph nodes was calcified and it was acid fast bacilli stain positive. Representative
images from four patients are shown in [Fig. 1].
Fig. 1 a Tubercular lymph node. b Histoplasma positive lymph node. c, d Left adrenals positive for Histoplasma.
Adverse events were encountered in 4 % of the patients. Two developed mild hepatic
encephalopathy related to sedation and both had Child’s C cirrhosis and were inpatients
at the time of the procedure. All of the possible precipitating factors for hepatic
encephalopathy including infection, bleeding, constipation, dyselectrolytemia, and
renal failure were excluded in these patients. None of the patients had clinically
significant bleeding.
Discussion
Patients with long standing PUO in the setting of cirrhosis pose a diagnostic challenge.
While patients with compensated cirrhosis may have normal coagulation parameters,
the presence of decompensated cirrhosis is associated with coagulation abnormalities
and collaterals. Diagnosis of the etiology of pyrexia is of utmost importance in patients
with cirrhosis. The correct diagnosis has multiple implications: first treatment of
the cause may lead to improvement in symptoms, and treatment of infectious disease
is important before liver transplant (if needed) to prevent flare up after transplantation.
Patients with liver cirrhosis are at increased risk of tuberculosis and also their
prognosis is worse [10]
[11], thus, timely diagnosis is important. Empirical ATT is often used in such patients;
however, these patients have a higher risk of hepatotoxicity that may lead to acute-on
liver failure which is associated with high mortality. Also, monitoring of drug-induced
hepatitis is confounded by the presence of cirrhosis due to fluctuating liver function
tests [12]
[13]
[14]. Patients with cirrhosis are immunosuppressed and thus may be more prone to develop
histoplasmosis as shown in the current series [15]. There are no large published studies on FNA in patients with decompensated cirrhosis.
EUS offers several advantages over other imaging modalities. It provides the option
for real time FNA, and vascular structures can be avoided as seen in [Fig.1c]. EUS also allows sampling from locations which are difficult to access by the percutaneous
route. Obtaining a tissue diagnosis is also important to avoid a delay in diagnosis.
Ten patients in the current series had tuberculosis. Three adrenal FNAs were performed
in the current series and the procedure is safe as shown earlier by our group in non-cirrhotic
patients [16]. It is important to work-up these patients by other means if EUS guided FNA is unable
to provide a diagnosis as one of the patients in the present series who provided an
inadequate sample had lymphoma.
We encountered mild hepatic encephalopathy as an adverse effect related to midazolam.
A recent meta-analysis by Tsai et al. suggested that propofol sedation for endoscopy
in cirrhotic patients provides more rapid sedation and recovery than midazolam, and
efficacy is also superior. The risk of sedation-related side effects for propofol
does not differ significantly from that of midazolam [17].
The strengths of the present study include its prospective nature and follow-up of
patients. It is the first such kind of study that expands the horizons of EUS guided
FNA. The sample size is small, however, as cirrhosis and long standing pyrexia are
very uncommon indications of EUS guided FNA. The findings of the current study may
not be applicable in Western countries where the prevalence of tuberculosis is low.
In conclusion, we present a series of 46 patients with cirrhosis who underwent EUS
guided FNA of the lymph nodes or adrenals and management was modified in approximately
one-third of the patients.
