Antituberculosis Induced DRESS Syndrome in a Pediatric Latent TB Infection

Overdiagnosed as TB Disease
Wiwiek Setiowulan,1 Redi Rulandani,2 Hana Sofia Rachman3
1
Department of Pediatrics, Muhammadiyah Hospital – Faculty of Medicine Bandung Islamic University, Indonesia
2
Intern Doctor, Department of Pediatrics, Salamun Hospital Bandung
3
Department of Pediatrics, Al Ihsan General Hospital - Faculty of Medicine Bandung Islamic University, Indonesia

Abstract
Pediatric drug reaction with eosinophilia and systemic symptoms (DRESS) is a life-threatening
uncommon disease that can be difficult to diagnose. Several drugs, mainly antiepileptics and
antibiotics, have been reported as the causative agents, but no case of antituberculosis treatment
(ATT) induced pediatric DRESS has been reported. We present a case of a 10 year old girl with
ten days of high fever during her fifth week of ATT (consisted of isoniazid, rifampicin, and
pirazinamid), followed by appearance of pruritic morbiliform rash and severe liver injury. The
fever decreased after discontinuation of the ATT and oral steroid administration, followed by
resolution of other symptoms. The diagnosis of TB disease in this patient was made in primary
health care using pediatric TB scoring system. Despite the total score of 6 (positive tuberculin test
and TB exposure), she has normal chest X-ray and no symptoms of TB. Therefore, the patient has
latent tuberculosis infection (LTBI) but overdiagnosed as TB disease. Due to the negative HIV
status of the patient, TB prophylaxis is not indicated. Reintroduction of ATT was not performed,
which led to lack identification of specific drug causing DRESS in this case.

Keyword: antituberculosis treatment, drug reaction with eosinophilia and systemic symptoms,
latent tuberculosis infection.
 Introduction

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug induced
hypersensitivity syndrome (DIHS), is a rare but severe drug reaction with mortality rate up to 10%.
The features consist of fever, rash, abnormal hematologic findings (eosinophilia, leukocytosis,
atypical lymphocytes), lymphadenopathy, and visceral involvement (hepatitis, pneumonitis,
myocarditis, pericarditis, nephritis, and colitis). The estimated incidence of DRESS ranges from 1
in 1000 to 1 in 10,000 drug exposures and more prevalent in adult than pediatric patients. The
pathogenesis of DRESS is believed to be a combination of delayed hypersensitivity type IVb,
genetic susceptibility, and drug-virus interaction.

Many drugs have been implicated to induce DRESS in children, such as antibiotics
(trimethoprim-sulfamethoxazole, vancomycin, amoxicillin-clavulanic acid), antiepileptic
medications (valproic acid, lamotrigine, carbamazepine, phenytoin), ibuprofen, nevirapine,
acetylsalicylic acid, griseofulvin, fluoxetine, and sulthiamine. Although antitubercular drugs such
as isoniazid, rifampicin, streptomycin, and pyrazinamide are known to cause DRESS among
adults, there is still no report of this occurrence in pediatric patients.

Tuberculosis among pediatric patients is prevalent in Indonesia with first line treatment consist
of 6 months isoniazid + rifampicin and two months pyrazinamide during intensive phase.
Establishing TB diagnosis in children is a challenge due the low rate of bacterial confirmed case.
This problem has led to developmental of a Pediatric TB Scoring System by the Indonesia Pediatric
Society; which a total score ≥ 6 is diagnosed as clinical TB. However, the sensitivity and specificity
of this scoring system is low (47% and 68% respectively) which may cause a lot of under or
overdiagnosis cases.

We present a case of ATT induced DRESS in pediatric patient in her fifth week of treatment.
Her mother was diagnosed with positive sputum smear tuberculosis and was also on her fifth week
of therapy when she had similar symptoms as the patient but died subsequently.

A ten year old girl was admitted to our hospital with 7 days of remittent high fever, mostly
during the nights, accompanied with headache, nausea, mild cough, and constipation. She appeared
weak and lost 1 kg during the course of illness. The patient was on the fifth week of
antituberculosis treatment (ATT) consisting of isoniazid, rifampicin, and pirazinamid in a primary
health care. The diagnosis of tuberculosis was made in a primary health care during households
contact investigation from a tuberculosis case using TB scoring system (score 6). Her mother had
AFB positive tuberculosis (score 3) and tuberculin skin test (TST) of the patient was positive (score
3). The patient showed no TB signs or symptoms and her chest X ray was normal. Her HIV status
was negative.
On admission, she was moderately ill, alert, BP 100/70 mmHg, pulse rate 64x/min, RR
24x/min, and temperature 38,7C. Her body weight was 26 kg, her height 138 cm, BMI 13.1
(moderately malnourished). She had typhoid tongue, liver enlargement 3 cm below processus
xyphoideus, and other physical examination was within normal limit. The CBC was normal
(hemoglobin 12,6 g/dL, hematocrit 36%, leucocyte 5.200/mm3, thrombocyte 203.000/mm3) and
ALT/AST was 29/68 respectively. Although the widal test was negative (S. typhi O and H 1/80,
S. paratyphi B O and H 1/40, S. paratyphi C H 1/40), due to the high endemicity of this disease,
the patient was diagnosed with typhoid fever and treated with ceftriaxone. Her ATT was
continued.
After four day of ceftriaxone the fever persisted and the patient developed generalized
morbiliform rash that began on the trunk and symmetrical on upper extremities. It was mildly
pruritic initially but became more severe on the next day. The eruption also became more apparent
and progressed caudally. Drug fever due to ceftriaxone was suspected. The medication was
discontinued and changed into azithromycin. Not only that the fever persisted, the generalized rash
on her body showed no improvement with cetirizine administration and another rash appeared on
the face mimicking the butterfly rash from systemic lupus erythematosus (SLE). Other signs of
SLE as arthritis, stomatitis, dst… not present.
The patient's father then informed us that her mother had the same symptoms as her daughter
before she was deceased. She was also on the fifth week of ATT when she developed a week of
high grade fever, followed by appearance of pruritic rash. The difference was, the mother became
jaundice, unconscious, and died three days later. We then suspected a severe drug reaction in the
mother and the patient. We still had to rule out any infection and possibility of drug induce lupus
erithematosus (DILE) in the patient.
To confirm the diagnosis of typhoid fever, a five days apart serial widal test was taken and
showed no increased results. We assumed that the fever in this patient might be due to other cause
than typhoid. The repeat CBC result: hemoglobin 11.5 g/dL, hematocrit 33%, leucocyte
6.900/mm3 (diff count: -/9/2/43/39/7), thrombocyte 247.000/mm3. However, her CRP result was
high (40 mg/dL), so was her ESR (35/60 mm/hour). We suspected a blood stream nosocomial and
added amikacin. Urinalysis, electrocardiography, and chest X ray was performed to rule out signs
of SLE and revealed normal results.

Although the patient wasn't jaundiced and only vomited once a day after meal, she appeared more
lethargic than before so we repeated her liver function tests. Surprisingly, her ALT and AST
increased to 830 and 1178 from relatively normal range in only just 8 days.
A diagnosis of DRESS was established on the eight day of hospitalization. Her ATT was stopped
and the fever disappeared in two days. To treat the rash, we gave her oral corticosteroid in
conjunction with ethambutol and streptomycin, which resolved dramatically in just one day. The
recovery of the patient's condition was quite dramatic. She appeared well and gain a good appetite
on the following days. After we received negative results from ANA - anti ds DNA test, the
corticosteroid, ethambutol, and streptomycin was discontinued. We gave her ursodeoxycholic acid
to treat the liver injury. She was discharged a week after the ATT discontinued with serial liver
function tests had already decreased by twofold. He liver function tests normalized within two
weeks. During the last visit, she had gained 1.5 kg and returned to her normal nutritional status.
We gave a note to the primary health care prescribing her the ATT that she had latent tuberculosis
infection (LTBI) and not TB disease. Therefore the ATT should be discontinued. There was no
indication for prophylaxis treatment because her age was above five years old and her HIV status
was negative.

Discussion

A diagnosis of drug fever, let alone DRESS, was not considered in this patient on admission
because the patient was presented with classical symptoms of typhoid, such as remittent fever with
peak temperature during the nights, headache, nausea, constipation, malaise, relative bradycardia,
and hepatomegaly (WHO). Widal test has a low sensitivity (73.5%), therefore the result in this
patient was initially considered as false negative and antibiotic treatment for typhoid was started.
Defervescence of fever in typhoid treated with ceftriaxone occur within 4-6 days (Crump 2015,
Nair 2017), which cause a delay in diagnosis of drug fever. Blood culture and Tubex test was not
performed in this patient due to financial reason (the patient wasn’t covered by The Indonesian
National Health Insurance System during this hospitalization).

Drug fever is easily mistaken as typhoid fever because the patient also has relative bradycardia, a
condition that occurs when the heart rate does not increase to the extent that typically accompanies
the temperature elevation. This is widely known to be a patognomonic sign of typhoid fever.
However, unlike typhoid, various patterns of fever may occur in patients with drug fever,
including: continuous fevers; remittent fevers, in which temperatures vary but are consistently
elevated from normal; intermittent fevers, which are interrupted by daily normal temperatures; and
hectic fevers, which manifest as a combination of intermittent and remittent fever patterns. Hectic
fever is the most common pattern of drug fever.

Patients with drug fever often appear “inappropriately well” for the degree of fever that they have.
This patient appeared moderately ill with malaise which inconsistent with the typical sign of drug
fever.

On admission, the complete blood count in this patient was normal. Unfortunately the leucocyte
differential count was not performed. Most patients with typhoid fever have relative
lymphocytosis, eosinopenia, moderate anemia, and thrombocytopenia. While in drug fever,
eosinophilia is frequently found and leukocytosis with or without a shift to the left may be present.
In both typhoid and drug fever, mild elevation of the erythrocyte sedimentation rate and hepatic
transaminase levels may occur, which are observed in this patient.

Persistence of fever after 4 days antibiotic treatment followed by pruritic morbiliform rash prompt
a suspicion of drug reaction. Ceftriaxone was considered as the causative agent and was replaced
with azithromycin, which is proven to be equivalent or superior to ceftriaxone for the management
of uncomplicated typhoid fever. (Crump 2015) However, no decline of fever and worsening
symptoms of rash despite antihistamine therapy concludes that drug reaction due to ceftriaxone
was unlikely.

Evaluation whether typhoid was the correct diagnosis in this patient was also problematic. A serial
Widal test is supposedly to be taken 10 days apart and a positive result is determined by a 4-fold
increase in antibody titer, which in practice is very difficult to do. On the other, discrepancies of
two Widal test results with 5 day interval in this patient proved why this test has been associated
with some controversies, including the inherent variabilities and lack of reproducibility of the test.
(Olopoenia 2000)

Vigorous effort to find any source of infection as the cause of fever in this patient was not
performed. Although not specific for infection, increase in C-reactive protein (CRP) and blood
sedimentation rate (BSE) test in this patient justify the decision to continue empirical antibiotic
treatment. However, as a sign of inflammation, a rise in CRP is also observed in drug fever, which
in rare case may be as high as 150 mg/dL (range:… ). (Palraj 2018)

The history of fever followed by rash, jaundice, and encephalopathy in the patient’s mother who
was also in her fifth weeks of ATT therapy led us to the diagnosis of DRESS by doing some
literature research. It is an uncommon condition with an estimated incidence that varies between
1:1000 and 10,000 drug exposures. Its prevalence is higher in adults than in children which may
cause pediatricians insufficiently aware of this condition, such as in this case. (Castellazzi 2018)
The pathogenesis of DRESS syndrome is not well understood. It is hypothesized to be a
combination of delayed T-cell-dependent hypersensitivity reaction to drug, genetic susceptibility,
and virus-drug interaction associated with viral reactivation (e.g. Epstein-Barr virus, HHV-6,
HHV-7, and cytomegalovirus).

The presence of DRESS syndrome in both mother and daughter shows that genetic susceptibility
is very likely to play an important role. Human leukocyte antigen (HLA) has been associated with
several drug hypersensitivity, such as HLA-B*1502 with carbamazepine induced Steven Johnson
Syndrome (SJS)/toxic epidermal necrolysis (TEN) and HLA-B*1508 with allopurinol induced
SJS/TEN. An association between HLA Cw*0401 and antituberculosis induced DRESS was
observed. (Kim 2012)

Virus-drug interaction could not be proven in this case because no viral serology test was
performed. However, a suspected typhoid fever preceeding drug fever in this patient prompt a
question whether an interaction between drug and other pathogen than viruses (possibly
Salmonella typhii) may also trigger a drug fever.
It is still not clear whether the first sign of fever in this patient was a part of DRESS syndrome or
due to other cause, which is clinical typhoid fever. Median onset of fever in DRESS syndrome is
one day before to three days after the onset of skin rash. However, it can occur as early as ten days
before the onset of rash. The long duration between fever and onset of rash may cause a prolonged
delay in diagnosis of DRESS.

The RegiSCAR (multinational registry of severe cutaneous adverse reactions) study group has
developed a diagnostic score which classify potential cases of DRESS as definite, possible, and no
case. Using this scoring system, based on the presence of fever ≥ 38.5 C (0), skin rash extent >
50% (1), one internal organ involvement (hepatitis = 1) this patient is categorized as a possible
case. Although the differential count showed increased eosinophil, it still didn’t meet the criteria
for eosinophilia. (Kardaun 2013)

Drug eruption, unlike DRESS, is known to be a common adverse effect of ATT in children.
However, it usually occurs within 2 weeks of treatment. This different course of disease is also
one of the causative factors of delayed diagnosis of DRESS in this patient.
A retrospective analysis in 78 patients with ATT induced fever showed that the most common
causative agent is rifampicin, followed by p-aminosalicylic acid (PAS), rifapentine (Rft), and
Pyrazinamide (PZA). Time of fever onset was not specific with rifampicin, either within 72 hours
or among 1-2 months. No ATT induced fever was reported after 2 months of drug administration.
The youngest patient with drug fever in this report is 9 years old but unfortunately the number of
pediatric patient with ATT induced fever or any progression into DRESS in this age group was
not mentioned. We also failed to find any case report of ATT induced DRESS in pediatric patients.

Cases of DRESS in pediatric patients have been reported with valproic acid, allopurinol, aspirin,
lamotrigin, vancomycin, and minocycline as causative agents. (Cacoub 2011, Verrotti 2002,
Dewan 2010, Vinson 2010, Kawakami 2009)

The root of the problems in this patient was the overdiagnosis of tuberculosis, which led to
unnecessary antituberculosis treatment that cause DRESS syndrome. All primary health care
facilities (puskesmas) in Indonesia must adhere to government TB DOTS program, which strictly
apply a score of ≥ 6 to diagnose pediatric TB. The important issue in the implementation of this
scoring system is in the context of household contact investigation in patients with positive sputum
smear. The scoring system gives a score of 3 for a history of close contact with such patient and a
score of 3 for a positive TST result. Therefore, children with household contact but have no
symptoms, normal CXR, and positive TST will have a total score of 6.

A new revised technical guidelines for diagnosing pediatric tuberculosis has been published in
2016 (?) but it has not been widely disseminated among primary health care in Indonesia. This
guideline show an algorithm when clinician find a total score 6 which consists of positive contact
and TST alone, the patient was considered to have latent TB infection, not TB disease. The TB
prophylaxis program in Indonesia is only targeting children below 5 years old, any children with
HIV positive or immunocompromised condition who have positive TST to receive prophylaxis
treatment.
 Drug fever is an adverse reaction that is frequently not recognized with estimated incidence.
A rare but severe and life threatening form of drug fever referred to as DRESS (drug reaction with
eosinophilia and systemic symptoms). The mortality rate of DRESS is around 10% a