CASE ANALYSIS

This case was a girl, 14 years 3 month old, with body weight 50 kg and
height 153 cm. This patient were diagnosed with acute myeloblastic
leukemia, ang lung tuberculosis.
Leukemia is a malignant disease of blood cells derived from bone
marrow, characterized by the proliferation of white blood cells with the
manifestation of abnormal cells in the peripheral blood. Acute leukemia is
the most common malignancy in children and accounts for 97% of all
leukemia in children. Acute leukemia can be divided into acute
lymphoblastic leukemia (ALL) 82% and acute myeloblastic leukemia
(AML) 18%.1,2 AML is characterized by neoplastic transformation and
differentiation of progenitor cells from the myeloid series. 3 AML incidence
among children in the United States in 2005-2009 was 7.7 cases per
1,000,000 children aged 0-14 years and continues to increase every year. 4
In Pediatric Department of Faculty of Medicine, University of Indonesia-
Cipto Mangunkusumo Hospital recorded cases of acute leukemia, only
426 out of 741 (57.5%) malignant cases were diagnosed between 2007-
2010, and AML was found in 93 children or 21.8% 5 The incidence of AML
in Sardjito’s Hospital in Yogyakarta was 8 per 100,000. 6
The cause of children’s leukemia is still unclear but many risk
factors are thought to be contribute to this disease. Risk factors can be
genetic predisposition and environmental factors. Genetic factors such as
Down syndrome, Bloom syndrome, ataxia-teleangiectasia and Fanconi
syndrome have a higher risk for leukemia. Environmental factors such as
ionizing radiation, drugs, paint or gasoline exposure, high voltage
electricity, viral infections and maternal exposure during pregnancy
(pesticides, cigarettes, alcohol and drugs) can also affect leukemia. 7-9 In
this case there is no genetic and environmental risk factors.
The diagnosis of AML can be established based on clinical
symptoms and laboratory investigations. 1 Clinical symptoms in AML such
as pallor, fever, infection, bleeding, bone pain, enlargement of liver and
spleen. Gum hypertrophy or parotid gland enlargement is rare but this is a
suggestive finding. Localized mass of leukemia (chloroma) cells can occur
anywhere such as retroorbital area.10,11 Study by Lima et al12, in Brazil for
patients aged <15 years in Brazil found frequent symptoms and clinical
signs are fever and decreased appetite. Table 1 shows the percentage of
AML clinical signs and symptoms in children.12

Tabel 1. Clinical signs and symptoms in AML patient 12

Clinical Signs and Symptoms Percentage (%)
Fever 41.10
Asthenia/ decreased appetite 35.20
Manifestations of bleeding 27.40
Pale 25.40
Bone Pain 21.50
Organ enlargement 7.80
Respiratory symptoms 7.80
Gum hypertrophy 5.80
Lymph node enlargement 3.90
Abdominal pain 3.90

Diagnosis in this patient is based on anamnesis, physical

examination and laboratory examination. The complaints in this patient
were fever since 2 days before admission and palor since 1 weeks before
admission. On the 2nd day of care, the patient developed nose bleeding
There were anemic conjunctiva, enlarged right anterior neck lymph node
diameter 2 cm, immobile, and hepatosplenomegaly from physical
examination.
Laboratory examination in AML include complete blood
examination, peripheral blood smear, and bone marrow aspiration
morphologically, immunophenotype and genetic characteristics. The initial
full blood examination in this patient showed anemia, leukocytosis and
thrombocytopenia. The peripheral blood smear in this patient showed
leukocytosis which dominated by myeloid series with 37% blast and also
showed thrombocytopenia.
 The definitive diagnosis of leukemia is confirmed by examination of
bone marrow aspiration, which shows a blast cells 44%. Based on
lineage-associated phenotype and defined by the French American British
(FAB), the classification of AML morphology can be divided into 8 types
namely M0, M1, M2, M3, M4, M5, M6, M7. Examination of
immunophenotyping is useful to determine the type of AML cells, that are
useful for determining choice of management and prognosis. 13,14 The
results of bone marrow morphology examination in this patient showed a
predominant myeloblast, 60% with hypercellular cell density,
erythropoiesis activity, granulopoiesis, and depressed trombopoiesis. The
conclusion is appropriate to AML. The results of immunophenotyping
showed gating on the blast area positive with CD 33, CD 34, CD 117,
HLA-DR, CD 13, CD. The conclusion was Mieloid Lineage appropriate
with AML.
Anemia in AML can occur because of hematopoiesis supression in
bone marrow due to blast cells infiltration. It is also can caused by
chemotherapy. Study by Janus et al15 shows that pallor in physical
examination in conjunctivae, tongue, hand palm and nail have 93%
sensitivity and 57% specificity for diagnose anemia with haemoglobin
below than 5 g/dL. Anemia is defined by haemoglobin concentration below
than normal haemoglobin concentration according to age (below than
average -2 standar deviation in normal population). Anemia cause
decreased the ability to carry out oxygen in blood and supply to tissue. 15,16
Management of leukemia include supportive and curative
treatments. Supportive care is needed include the treatment of
comorbidities and complications such as blood or platelet transfusion,
antibiotics, anti-fungal drugs, optimal nutritional support and psychosocial
aspects. Curative or specific therapy aims to eradicate leukemia cells in
both the bone marrow and outside the bone marrow and provides an
opportunity for the bone marrow to function normally. Therefore, the
chemotherapy is administered aggressively by administering a
combination of several chemotherapy drugs. 1,17 Supportive management
of this patient includes blood transfusion, platelet transfusion, nutritional
support according to the RDA and psychosocial approach. For curative
management, the patient received chemotherapy according to National
Pilot Protocol of Indonesian Childhood AML (revised 2015).
Chemotherapy agents consist of anthracyclines, cytarabine, methotrexate,
etoposide.
The mechanism of action of chemotherapeutic drugs is not
selective, in addition to the eradicated cancer cells, normal cells such as
bone marrow, gastrointestinal tract, hair follicles, and the reproductive
system are also affected. Some side effects of chemotherapy may occur
unexpectedly during chemotherapy. The mechanism of action of
chemotherapy that is not selective and combination therapy causes
increased drug toxicity. Chemotherapy toxicity in general can be divided
into acute and long-term toxicity. Acute toxicity will occur immediately after
chemotherapy (hour-week) and is temporary, whereas long-term toxicity is
permanent. Some chemotherapy drugs are unique because drug toxicity is
specific to certain organs or tissues. Common side effects of cytostatic
include nausea, vomiting, alopecia, pain, myelosuppression (anemia,
neutropenia, thrombocytopenia), mucositis, blepharitis,
immunosuppression and adverse effects on organ systems affected by
cytostatic agents.18,19
Decreased platelet production is common in patients with AML due
to direct tumor involvement of the bone marrow. Thrombocytopenia is
most often the result of systemic cancer treatment. The mechanism by
which chemotherapy drugs cause thrombocytopenia is megakaryocyte
cytotoxicity. Neutropenia is frequently occur in pediatric patients receiving
chemotherapy. Neutropenia also can occur due to disruption of neutrophil
formation, neutrophil shift to tissue, increased neutrophil consumption and
increased neutrophil destruction in the circulation. This is a potentially life-
threatening condition and requires immediate medical intervention.
Despite the great advances in prevention and treatment, neutropenia
remains one of the most alarming complications of cancer chemotherapy
and is one of the leading causes of morbidity.20,21
Febrile neutropenia (FN) is an oral temperature of > 38.3 °C or two
consecutive readings of > 38.0 °C for 2 hours and an absolute neutrophil
count (ANC) of < 0.5 × 109/l, or expected to fall below 0.5 × 10 9/l .In cancer
patients, it is a serious, potentially fatal condition complicating cancer
treatment associated with significant morbidity and mortality and common
22
reasons for hospital admission in children with cancer. This patient have
fever and ANC < 500 that indicated the existence of febrile neutropenia.
Patients with fever and neutropenia can be categorized as low-risk
and high-risk for severe infection or complications based upon presenting
signs and symptoms, absolute neutrophil count (ANC), underlying cancer,
anticipated duration of neutropenia (varies with type of chemotherapy),
and medical comorbidities. Low-risk patients are those with all of the
following:
- Neutropenia expected to resolve within seven days (ie, neutrophil
count increasing)
- Stable and adequate hepatic and renal function
- No active comorbidities (eg, hemodynamic instability, mucositis,
gastrointestinal symptoms)23,24
For children at low risk of serious infection, several studies using strict
eligibility criteria suggest that outpatient treatment may be safe and
appropriate. When children with fever and chemotherapy-induced
neutropenia are treated as outpatients, they will be given first dose of
antimicrobial therapy in a clinical or hospital setting and be observed for
≥4 hours before discharge. They should be readmitted for hemodynamic
instability, signs and symptoms of new or worsening infection, or, in the
absence these, persistent fever (ie, >48 to 96 hours).Children with fever
and chemotherapy-induced neutropenia who are low risk for serious
infection or complications and are not candidates for outpatient therapy
are hospitalized for IV broad-spectrum monotherapy
with cefepime, meropenem, or piperacillin-tazobactam. 23
 High-risk patients have an increased risk of severe infection or
complications and should be admitted to the hospital for empiric
antimicrobial therapy. Patients with any of the following to be high risk 25:
- Neutropenia (ANC <500 cells/microL) anticipated to last >7 days
- Evidence of hepatic insufficiency (aminotransferase levels >5 times
normal values)
- Evidence of renal insufficiency (creatinine clearance <30 mL/min)
- Comorbid medical problems including, but not limited to:
 Hemodynamic instability
 Oral or gastrointestinal mucositis that interferes with
swallowing or causes diarrhea
 Gastrointestinal symptoms, including abdominal pain,
nausea, vomiting, or diarrhea
 New-onset neurologic or mental status changes
 Signs of intravascular catheter infection, particularly catheter
tunnel infection (eg, erythema, swelling, and/or tenderness at
the insertion site, rigors or chills associated with catheter
flushing)
 New pulmonary infiltrate or hypoxemia or underlying chronic
lung disease
 New findings or symptoms associated with localized infection
- Infants with acute lymphoblastic leukemia
- Patients with acute myeloid leukemia
- Patients within 30 days of hematopoietic cell transplant (HCT)
For high-risk children with fever and chemotherapy-induced
neutropenia who are clinically stable and in whom there is no suspicion of
resistant infection (eg, methicillin-resistant S. aureus [MRSA]), we
recommend initial broad-spectrum monotherapy with an antipseudomonal
beta-lactam agent (eg, cefepime 50 mg/kg IV every 8 hours up to
maximum 2 gr per dose or meropenem 20mg/kg IV every 8 hours up to
maximum 1 gr per dose, or piperacillin-tazobactam for patient weight >40
kg, 3 g IV every 6 to hours) to provide activity against the pathogens that
are associated with serious or life-threatening infections in neutropenic
patients.26 This patient is classified as high-risk febrile neutropenia
because she has acute myeloid leukemia and her ANC was 0. She was
given meropenem 1gr every 8 hours.
In AML patient, should be given prophylaxis for antifungal and
antibacterial because of intensive myelosuppresive chemotherapy
regimens increase the risk of infection. Pediatric consensus guidelines
recommend fluconazole 6-12 mg/kg/day for children with AML.
Pneumocystis jiroveci is a yeast-like fungal species which causes
pneumonia in patient with malignancy. Prophylaxis with trimethoprim-
sulfamethoxsazole (TMP-SMX) remains the standar of care and is
generally continued for 3 months after completion of chemotherapy. TMP-
SMX is given at a dose of TMP 5 mg/kg/day divided BID. 27
The effectiveness of leukemia treatment can be seen from survival
rate. By following the course of the disease we can predict how long the
patient can survive and factors that affect the duration of a patient's
survival. In leukemia patients, the survival rate used as a benchmark is a
5-year survival rate. If a person with leukemia can survive for 5 years
since receiving treatment then the patient may be declared cured of
leukemia.28
Tuberculosis (TB) is an infectious disease caused by Mycobacterium
tuberculosis. TB is the leading cause of children morbidity and mortality in
developing countries. The World Health Organization (WHO) estimates
that TB leads to 1.8 million deaths and 10.4 million new cases annually.
One million of these cases and 210,000 deaths occur in children. TB is
widely suffered illness in many developing countries like Indonesia.
Indonesia currently is the 3 rd country with the most cases in the world. In
the 2014 Global Tuberculosis report released by World Health
Organization (WHO) mentioned that TB incidence in Indonesia is 460,000
new cases per year. However, in a similar report in 2015, the figure has
been revised based on a survey since 2013, it becomes up to 1 million
new cases per year. The percentage of cases in Indonesia becomes 10
percent of all cases in the world.29-31
The recent studies showed that adolescents are a vulnerable age
group with a higher chance of developing pulmonary TB disease
compared to younger children. The prevalence of TB increased by
increasing age, the most prevalent age for infection was the adolescent
period (15 - 18 years) with the mean age was 15,6 years and the second
peak occurred in the 10 - 14 years. Hormonal changes and altered protein
and calcium metabolism associated with adolescent growth contribute to
increased risk for tuberculosis. The endocrinal effect changes the disease
nature through immune system and shortens the time interval between
initial infection and the development of active disease. 30,31
Tuberculosis amongst adolescents is distinct from both childhood and
adult tuberculosis in terms of incidence, disease manifestations and
response. These peculiarities are due to issues related to immunity,
hormone imbalance, social interactions and psychology unique to this
phase of life. TB during adolescence presents unique challenges, both for
31,32
case detection and for management.
Among adolescents, TB was more prevalent in females (63.2%).
Female adolescents were more likely to have positive smear (88%),
cultural growth (63.6%) and drug resistant TB infection (71%). The
prevalence of TB increased by population of female patients also in
Zahedan, Iran. Another study by Kaushik et al, also found that the
incidence in females (1.00 %) was significantly more in comparison to
males (0.63 %) with females having1.60 times more odds of suffering from
Tuberculosis than males (p< 0.001).31
Transmission of pulmonary TB infection is commonly occured from
adult to child. In children who are in close contact or live with adult TB
patients, the risk of transmission of TB disease increases, especially those
under 5 years old or under immunocompromised conditions, densely
populated conditions, the severity of case sources determined by acid-
resistant bacteria (ARB) positive from patient’s sputum, abnormalities in
the lungs shown by radiology. Nevita et al find one of TB risk factors was
sleeping in the same house as a case of tuberculosis. The proportion of
cases of tuberculosis attributed to contact with someone with TB was
38%.33
This patient is a female, adolescent, and the risk factor of
tuberculosis transmission was exposure from mother with history of
infectious tuberculosis and AML in this patient caused decreased
immunity.
The pathogenesis of tuberculosis in children through three
important stages: exposure, infection and disease. TB exposure is the first
stage, which occurs when an individual has been in close proximity to a
person with contagious TB disease. The second stage is TB infection,
which occurs when an individual has inhaled the causative organism but
has no overt physical symptoms or findings on radiographic examination.
Following infection, all children progress through an asymptomatic
incubation period generally lasting 3–8 weeks. TB disease exists when an
individual manifests symptoms, signs, or radiographic manifestations
consistent with M. tuberculosis pathology and declines thereafter. 29
The subsequent development of clinical disease is determined by
the interaction of the host and the organism and is highly age-dependent.
It is presumed that these children are infected with a low number of viable
tubercle bacilli that do not immediately cause clinical disease. Once the
organisms are inhaled, they are ingested by alveolar macrophages, which
form caseating granulomas to contain the bacilli. Macrophages transport
some bacilli to the regional lymph nodes. Before an adequate immune
response is mounted, the bacilli can transit from the regional lymph nodes
via the lymphatic duct or directly into the systemic circulation. This occult
lymphohematogenous spread disseminates bacilli to various organs,
where they may survive for decades. Disseminated TB disease results if
the dissemination is not controlled by the developing acquired immune
response. The occult dissemination also provides the seed organisms for
extrapulmonary TB, which accounts for 20%–30% of childhood TB cases.
In some children, tubercle bacilli reach a terminal airway and induce a
localized pneumonic parenchymal inflammatory process referred to as the
primary (Ghon) focus. Approximately 70% of the primary foci are
subpleural. All lobes are equally affected, and 25% of children have
multiple parenchymal foci. Bacilli originating from this focus drain via local
lymphatics to the regional lymph nodes. The triad of the primary focus,
local tuberculous lymphangitis, and enlarged regional lymph nodes is
referred to as the primary complex. 29
The primary complex and its complications become apparent most
often 3–6 months after infection. It is common for untreated primary
complex TB to result in calcification of the lung parenchyma and/or
regional lymph nodes, a process that occurs at least 6 months after
infection. Although pleural and lymph node TB often develop within 3–9
months after infection, other extrapulmonary forms of TB, especially
skeletal and renal disease, may not develop for several years. 29

Primary Complexseveral
Bronchial erosion(3-9 Skeletal TB(in 3 years)
resolves on its own(3-24
months)
months)
MeningitisMiliary
Pleural TB(in 12 months) Renal TB(after 5
effusion(3-6 years)
months)
INFECTION

HYPERSENSITIVITY ACQUIRED IMMUNITY

POSITIVE TUBERCULIN SKIN TEST

2-12 weeks(6-8 1 year

weeks)

Highest risk for

Local complication and dissemination Lower risk

Figure 1. Primary Tuberculosis disease in Time Table.34

A primary focus, without or occasionally with cavitation, may be
seen in symptomatic children who have weight loss, fatigue, fever, and
chronic cough. If the host is unable to contain the tubercle bacilli,
progressive caseation occurs in the lung parenchyma surrounding the
primary focus. The area of caseation may discharge into a bronchus,
resulting in the formation of a primary cavity with possible endobronchial
spread. The tubercle bacilli disseminate further to other parts of the lobe
and can involve an entire lung. On rare occasions an enlarging primary
focus ruptures into the pleural cavity, creating a pneumothorax,
bronchopleural fistula, or caseous pyopneumothorax. Profound fever,
cough, and weight loss accompany a severe progressive lesion.29
Specific clinical manifestations depend on the affected organs. The
oftenly affected lymph glands are anterior or posterior lymph nodes of the
neck, it can also occur in the axilla, inguinal, submandibula, and supra
clavicle. The affected glands are usually multiple, unilateral, non-tender,
not warm on palpation, and can confluence with each other. When TB
bacteria involve neural tissue, the symptoms are usually associated with
cranial nerve disorders, headache, constipation, neck stiffness, and
seizures.34
TB in adolescents differs substantially from disease in younger
children. Adolescents are more likely to present symptomatically, as
opposed to being identifie during contact investigations. Adolescents were
evaluated at enrolment for symptoms of possible TB, defined as one or
more of the following: cough for 2 weeks, weight loss for ≥ 2 weeks, fever
for ≥ 2 weeks, night sweats for ≥ 2 weeks, or hemoptysis and exposure to
TB, defined as living in a household where a person had been diagnosed
with TB.35

Table 2. Symptoms of Children and Adolescent with Active Tuberculosis. 36

Complaint Percentage
Cough 23.6%
Fever 17.5%
Weight loss 16.1%
Night sweats 10.9%
Loss of appetite 10.2%
Dyspnea / respiratory failure 8.8%
Chest pain 5.7%
Hemoptysis 3.1%
 Abdominal pain / distension 2.3%
Headache / seizure / muscle weakness 0.8%
Generalized lymphadenopathy 0.6%
Neck mass 0.3%
Back pain 0.2%

In this patient, the clinical manifestations are cough, hemoptysis,

decreased appetite and weight loss. There was enlarged right anterior
neck lymph with diameter of 2 cm, immobile, painless.
Chest radiography was the first diagnostic test outside of stain and
culture that assisted in the diagnosis of TB. The most common
radiographic findings in primary pulmonary TB by recent infection in
previously healthy adolescents are upper lung lesions, which were thought
to be radiographic findings of reactivation pulmonary TB by remote
infection.Pulmonary TB in adolescents is sometimes characterized by
radiological evidence of cavitation in the upper lung and smear-positive
sputum in what has been termed adult-type pulmonary TB (ATpTB).
Primary TB infection can also manifest with upper lung involvement with
consolidation, nodules and cavitation in the form of disease known as
ATpTB.33,37,38
Table 3. Abnormal radiographic findings in primary pulmonary
tuberculosis in previously healthy adolescent patients. 39
Variables Percentage
Small nodules (D < 10 mm) 96%
Large nodules (10 mm ≤ D < 30 mm) 51%
Cavity 45%
Consolidation 25%
Hilar lymph node enlargement 2%
Mediastinal lymph node enlargement 0
Pleural effusion 0

In this patient, radiographic findings showed normal chest x rays.

The Tuberculin Skin Test remains the most widely employed test
for the diagnosis of TB disease and infection in children standard
reference material worldwide. It has existed in several forms, currently the
Mantoux test, which is the intradermal injection of 5 TU of purified protein
derivative (PPD) or 2 TU of PPD RT23. In response to the antigen, a
patient who mounts a cell-mediated response to tuberculin antigens has a
delayed-type hypersensitivity response, previously sensitized T cells
release lymphokines that induce local vasodilation, edema, fibrin
deposition and recruitment of other inflammatory cells. The reaction
begins 5–6 hours after injection and reaches maximal induration at 48–72
hours, the time when the test should be interpreted. Induration at the site
of the TST is caused by migration of mostly mono nuclear cells to the area
and the inflammatory process secondary to the response of these cells.
This response can be attributable to infection with M. tuberculosis,
exposure to NTM, or receipt of Bacille Calmette - Guérin (BCG) vaccine.
Subjects with exposure to environmental NTM typically have indurations
<10 mm. The WHO recommends use of a cutoff of 10 mm for most
children and a cutoff of 5 mm in immunosuppressed children. 39-40 This
patient has positive TST with induration diameter 20mm.
However, in 2010, the WHO endorsed the use of a newer PCR
method, the GeneXpert MTB/RIF assay (Xpert) (Cepheid, Sunnyvale,
California). GeneXpert MTB/RIF utilizes a heminested real-time PCR
assay to amplify an Mycobacterium tuberculosis-specific sequence of the
rpoB gene which is then probed with molecular beacons for mutations
within the rifampicin-resistance determining region. It can facilitate rapid
diagnosis from clinical specimens in 90 minutes time. The WHO
commissioned its use in resource-limited settings for both adult and
pediatric specimens as well as pulmonary and extrapulmonary specimens.
Innovative active case finding including the wider use of Xpert MTB/RIF is
needed to detect smear-negative TB among adolescents. Xpert's limit of
detection is 131 CFU/mL, as compared with smear's 5000–10,000
CFU/mL and culture's 10 CFU/mL. Given the paucibacillary nature of
childhood TB and the limited specimen volumes children can produce. 41,42
This patient has negative result for GeneXpert MTB/RIF assay with
the test result Mycobacterium tuberculosis not detected.
 Even in developed countries, the gold standard for diagnosis of
childhood TB is a triad of (1) an abnormal chest radiograph and/or clinical
findings consistent with TB, (2) a positive TST or IGRA result and (3) a
history of contact with an infectious TB case within the past year. If the
results of Drug- Susceptibility Testing (DST) on the organism isolated from
the contact case are available, obtaining a culture from the child adds little
sensitivity or specificity to the diagnosis if the triad is present. 29
Thus, similar to younger children, the clinical diagnosis of TB in
adolescents cannot be purely driven by microbiologic findings. Instead, the
diagnosis often will be made based upon compatible clinical, radiographic
or histopathologic findings, a positive tuberculin skin test (or positive
interferon-γ release assay), epidemiological risk factors for TB and
exclusion of alternate diagnoses.43
Treatment of TB disease is designed to prevent the complications
of disease in the host and the development of drug resistance in the
organism. Treatment of tuberculosis is carried out with the principles as
following:
 Drug must be given in the form of a combination of several types of
drugs, in sufficient quantities and the right dose according to the
category treatment. Don't use single drug (monotherapy). Use Fixed
Dose Combination (FDC) is more profitable and highly recommended.
 To ensure compliance with patients taking drugs, Directly Observed
Treatment (DOT) is done by a Drug Swallow Supervisor.
 TB treatment is given in 2 stages, intensive and advanced. 39
At the intensive stage (early) the patient gets medication every day
and needs to supervised directly to prevent the occurrence of drug
resistance. If intensive treatment is given appropriately, usually the patient
becomes non-infectious within a period of 2 weeks. Most patients with
positive smear TB become negative smear (conversion) in 2 months. In
the advanced stages patients get fewer types of drugs, however in a
longer period of time. The advanced stage is important to kill persistent
germs so that recurrence can be prevented.39
The most common regimen studied consisted of INH and RIF,
supplemented with pyrazinamide during the first 2 months. Most trials
used daily therapy for the first 2 months, followed by daily or twice-weekly
therapy to complete 6 months. In these trials, the overall success rate was
greater than 95% for cure and 99% for significant improvement during a 2-
year follow-up.29
In children with suspected INH-susceptible pulmonary TB, the
recommended treatment is a 6-month regimen consisting of INH and RIF,
supplemented during the first 2 months with pyrazinamide. The first 2
months of multidrug therapy are frequently referred to as the intensive
phase. Daily administration of the regimen during the first 2 weeks to 2
months may be followed by at minimum twice-weekly therapy to complete
6 months, a period referred to as the continuation phase. 29
In children or adolescents with adult-type pulmonary TB or
epidemiologic circumstances suggesting an increased risk for infection
with an organism that is resistant to INH, the American Thoracic Society
(ATS) in concordance with National Control Program Tuberculosis in
Indonesia Category 1, recommends an initial 2-month treatment phase
consisting of daily administration of four drugs: INH, RIF, pyrazinamide,
and ethambutol. This initial treatment is followed by 4 months of INH and
RIF twice-weekly. Category 1 Tuberculosis drug for are provided in the
form of a fixed dose combination drug (FDC drug). This FDC tablet
consists from a combination of 2 or 4 types of drug in one tablet. The dose
adjusted for the patient's weight.29
Table 4. FDC drug dose for Category 1 Tuberculosis (National Control
Program Tuberculosis in Indonesia).39
Intensive stage Advance stage
Body everyday for 56 days. (3 days in a week, for 16
Weight RHZE (150/75/400/275) weeks)
RH (150/150)
30-37 kg 2 FDC tablets 2 FDC tablets
 38-54 kg 3 FDC tablets 3 FDC tablets
55-70 kg 4 FDC tablets 4 FDC tablets
>71 kg 5 FDC tablets 5 FDC tablets

This patient was taking treatment since 3 months ago. In this

advance stage she was treated using FDC drug according to her body
weight. This patient was given 3 FDC tablets daily. Each FDC consist of
Isoniazid 75mg, Rifampicin150mg.
Because INH competitively inhibits pyridoxine metabolism, resulting
in a peripheral neuritis, pyridoxine (5–10 mg/day) is recommended for
infants, children, and adolescents treated with INH who have nutritional
deficiencies, symptomatic HIV infection, or diets low in milk or meat
29
products and in breastfed infants. The patients was also given Pyridoxin
10mg, 1 tablet daily.
Management of TB should be holistic. The success of TB therapy
aims to cure active TB disease without recurrence, prevention of drug
resistance, and ensure good quality of life by preventing further
complications. 43
The prognosis of childhood acute myeloid leukemia (AML) has
improved significantly over the recent decades, with survival rates
increasing from <10% only 40 years ago to about 70% today. 44 The risk of
relapse of childhood AML has decreased dramatically over the past 3
decades, from greater than 50% in the 1980s to less than 25% in the most
recent trials.45,46 Despite improvement in overall outcome, the timing of
relapse has not changed. In all treatment eras analyzed, the median time
to relapse was less than one year. Children with AML who remain in
complete remission for at least four years from the time of diagnosis have
an extremely low (<1%) risk of relapse.46
Access to care and supportive care have been reported to influence
the outcome of childhood AML. Furthermore, the outcome of AML in
developing countries has been reported to be inferior to those reported in
developed countries.47 Patients with ALL have a better prognosis, less
intensive treatment, lower relapse rates, and fewer treatment-related
deaths, factors that may have led to a different finding in ALL versus
AML.48 Approximately, 30% of pediatric patients relapse, with only 30–40%
of these relapsed patients surviving, indicating a poor outcome. AML is a
highly heterogeneous disease and through gaining knowledge on its
molecular and genetic background it will allow new targeted and patient-
specifc therapies to become available to children. 49
AML treatment continues to have long-term sequelae. In an
analysis of 77 AML survivors, there is previously reported that growth,
neurocognitive, and endocrine abnormalities were common, especially
among patients who underwent HSCT. A Childhood Cancer Survivor
Study analysis of 272 AML survivors who did not undergo HSCT indicated
that 50% of the survivors reported a chronic medical condition, greater
than 25% reported at least 2 conditions, and 16% reported a severe or
lifethreatening condition.49
A systemic review and meta-analysis by Cheng et al (2017) that
analyzed total of 23 studies reporting 593 tuberculosis cases occurring in
324 041 cancer patients between 1950 and 2011 found that Individuals
with hematologic, head and neck, and lung cancers had a 9-fold higher
rate of developing active tuberculosis compared to those without cancer
and would benefit from targeted latent tuberculosis screening and
therapy.50 (Level of evidence 2A, recommendation B)
A systemic analysis by Jain A et al, analyzed 26 cases of TB
complicating the course of acute leukemia (AL) between January 2015 to
January 2017. 26 patients of AL developed TB. The median time to
diagnosis of TB was 8 weeks (0–432 weeks) following the diagnosis of AL
and it was comparable between the three leukemia groups (AML, ALL and
APML). The diagnosis of TB required alteration of anti-leukemia therapy in
26.9% patients and rescheduling in another 42.3% patients. Therapy
alteration/rescheduling were more frequent in patients with AML as
compared to ALL and APML(acute promyelocytic leukemia) (p< 0.03, <
0.04). Disseminated TB was more common in AML patients (p< 0.016).
Mortality was directly attributable to TB in 10% patients. Managing
tuberculosis remains a challenge during treatment of acute leukemia. With
this analysis, we advocate for a need of early suspicion and evaluation for
TB in patients receiving treatment for acute leukemia. Rescheduling and
or alteration of anticancer therapy due to TB is associated with
significantly higher mortality.51 (Level of evidence 3A, recommendation B)
Shu CC et al do study that retrieved information and identified
patients with malignancy and TB between 2000 and 2015 from the
Taiwanese National Health Insurance reimbursement datasets, Taiwan
cancer registry and death registration. During study they reviewed
1,105,009 patients after exclusion and among them, 19,906 had newly
diagnosed TB. The TB incidence in cancer patients divided all TB events
increased annually, from 3% in 2000 to 13% in 2015. The standard
incidence rates (SIR) were highest in cancer of respiratory tract (5.45),
hematology (3.70) and then head and neck area (2.58). The mortality
directly due to TB was defined as 0.83% and all-cause mortality were
approximately 10.5% at 3 months and 20.56% at 12 months. After
completing TB treatment, recurrence was diagnosed in 626 (3.14%), and
1001 (5.03%) patients within the first and the first two years, respectively.
In conclusion, the incidence of TB in patients with malignancy increase
yearly as well as its proportion within overall cases. The twelve-month all-
cause mortality during TB and the two-year recurrence are as high as
20.56% and 5.03%, respectively.52 (Level of evidence 3A,
recommendation B)
Alam MM et al do a retrospective analysis on 872 hospitalizations of
pediatric cancer patients with Febrile Neutropenia. The mean age of the
study population was 5±4 years. Majority of them were males
(n=559,64%). Cause of neutropenia was identified in only 58 (43%)
patients, out of URTI (22%), BSI (7%), pneumonia (4%), infectious
diarrheas (2%) and UTI (1%). Age less than 5 year (p= 0.043), AML
(p=0.019), patients who received chemotherapy within 2 week of Febrile
Neutropenia (p=0.007), severe neutropenia ANC < 50/cm (p < 0.041),
platelets count < 50,000/cm (p < 0.027), Fungal infection (p <0.001), and
pneumonia were identified as risk factors associated with development of
Prolonged Febrile Neutropenia (> 5 days) in pediatric cancer patients. A
total of 25 (2.9%) patients were required PICU admission and overall 12
(1.4%) patients were expired. Both outcome variables were statistically
significant regarding PICU admission (OR: 5.4) and mortality rate (OR:
8.1) in patients with PFN versus FN respectively.53 (Level of evidence 3A,
recommendation B)
The prognosis in this patient is divided into an ad vitam prognosis,
ad functionam prognosis, and ad sanationam prognosis. Ad vitam, ad
functionam and ad sanationam prognosis in this patient is dubia ad
malam, because from the evidence finds low survival rates in AML patient
especially in developing countries.. Family education is essential to
achieve treatment success. The education that can be given to this patient
includes the condition of the patient, the treatment plan, and the course of
the illness. Good knowledge can hopefully create environment that can
support treatment process, optimal growth and development with a good
quality of life.
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