Tuberculosis in children

Zhi-min Chen

Dept. Pediatric Pulmonology ， Children’s Hospital

Email: zmchen@zju.edu.cn

Pediatrics

Tubercle bacillus

Oder Actinomycetales

Family mycobacteriaceae

Genus Mycobacterium(M.)

Species M. tuberculosis M. bovis Non-TB M.

Chronicle of Tuberculosis

1882 Discovery of TB(Robert Koch)

1921 BCG development

1944 Invention of streptomycin

1952 Invention of Isoniazid

1966 Invention of Rifampin

………

Characteristics

Acid-fastness

ziehi-Neelsen

Slow-growing

Unusual resistance

Multi-Drug Resistance strain(MDR)

Source of infection

Open Pulmonary Tuberculosis (adult)

acid-fast smear of sputum(+)

copious production of thin sputum

severe and forceful cough

extensive upper lobe infiltrate or cavity

Young children with TB rarely infect others

Route of transmission

By respiratory tract:

airbone mucus droplet nuclei

contaminated dustBy alimentary tract

raw milk

contaminated foodBy others: (Placenta,skin)

Transmission rarely occurs by direct contact with an infected discharge or contaminated fomite!

High-risk population

Genetic background:

twin

racial difference

HLA BW35Environmental factors:

socioeconomic status

overcrowding

poor nutrition

inadequate health care

TB infection and TB disease

TB infection:

inhalation of infective droplet nuclei containing

TB

A reactive tuberculin skin test and the absence

of clinical and radiographic manifestations

TB disease:

Signs and symptoms, or radiographic changes

become apparent

From TB infection to TB disease

Light J ,et al. Curr Probl Pediatr adolesc Health Care,2009; 39:61

Infection, disease or not

Virulence of the TB strain

The size of inoculin

The hypersensitivity of the individual tissues

Nutritional or social status

Immunologic status

Genetic background

Primary Pulmonary Tuberculosis

Pediatrics

Spreading of M.tuberculosis

Initial focus (local infection at the portal of entry)

Draining lymphatic vessles

Regional lymph nodes

Blood

Other tissues of the body

Primary pulmonary tuberculosis

Clinical types Initial focus

Primary complex lymphangitis

Lymphadenitis

Bronchial lymph node tuberculosis

Primary pulmonary tuberculosis

Clinical manifestation

Surprisingly meager(subclinical)

Infants more likely to develop signs and

symptoms

Nonproductive cough and mild dyspnea as the

most common symptoms

Primary pulmonary tuberculosis

Less common symptoms

Systemic complaints

fever, night sweats, failure-to-thrive,

anorexia, etc.

Bronchial irritation or obstruction

localized wheezing

Prognosis

Improve or dissolve

Completely resolution

Induration

Calcification

Local progress

Exacerbation

Tuberculous meningitis

Most common in children of 6mo~4yr

Usually develops during the lymphohematogenous

dissemination of the primary infection

High mortality and high morbidity

Tuberculous meningitis: Clinical manifestation

Stage 1: Prodromal stage

Stage 2: Transitional stage

Stage 3: Terminal stage

Stage 1: Prodromal stage

Lasts 1~2wk

Nonspecific symptoms: character

alteration, fever, headache, malaise,

irritability, drowsiness

Focal neurologic signs absent

Stage 2: Transitional stage

Increased intracranial pressure: headache,

projectile vomiting, papilledema

Meningeal irritation: nuchal rigidity, Kernig’s

sign, Brudzinski’s sign

Toxic appearance: fever, anorexia, nausea

Others: cranial nerve palsies, convulsion

Stage 3: Terminal stage

1~3wk

Exacerbation of neurologic symptoms

Very thin with scaphoid abdomen

Electrolyte imbalance

SIADH

Cerebral salt losing syndrome

Diagnosis

Laboratory study

Clinical diagnosis

Typical CSF picture of tuberculous meningitis, but NOT specific

Pressure

Appearance ground-glass

Cell counts 50~500×106/L, L. predominates

Protein

Glucose <40mg/dl ， or CSF/blood <50%

Chloride

Diagnosis

Laboratory study

isolation of M. tuberculosis: most specific

• Smear acid-fast staining

• Culture (BACTEC, liquid, coloricmetric)

• PCR and Gene probe

Diagnosis

Laboratory study

Isolation of M. tuberculosis

Serology: limited value

• LAM antibody

• 38kDa antibody

• 16kDa antibody

• … …

Diagnosis

Laboratory study

Isolation of M. tuberculosis

Serology

biopsy and histology : pathognomonic

• Caseous necrosis and encapsulation

Diagnosis

Laboratory study

Others

• INF-γ Releasing Assays( IGRAs): promising

– INF-γ produced by T-cell responses to

M.tb-special antigens called early secreted

antigenic target 6 (ESAT-6) and culture

filtrate protein10.

– Commercial kits: Quantiferon-TB Gold In-

tube (QFT) and The T-Spot TB (T-Spot) test

Diagnosis

Laboratory Study

Clinical diagnosis

History

Clinical manifestation

Tuberculin test

Roentgenographic examination

Therapeutic trial

Diagnosis

Laboratory Study

Clinical diagnosis

History: usually need chest film or CT of her parents or family members

Clinical manifestation

Tuberculin test

Roentgenographic examination

Therapeutic trial

Case report

6-month-old girl

Born in San Francisco, but her parents immigrated to

USA from China 8 yrs ago.

Chief Complaint

cough and fever for 3 weeks and tachypnea for 1 week.

No response to routine antibiotic therapy

Diagnosis

Laboratory Study

Clinical diagnosis

History

Clinical manifestation: Not specific

Tuberculin test

Roentgenographic examination

Therapeutic trial

Diagnosis

Laboratory Study

Clinical diagnosis

History

Clinical manifestation

Tuberculin test: more valuable

Roentgenographic examination

Therapeutic trial

Tuberculin test ： principle & method

Based on delayed type hypersensitivity( type IV)

Two antigen preparations:

Old tuberculin, OT

Protein purified derivative, PPD

Intradermal injection of 0.1ml containing 5

tuberculin units of PPD (Mantoux test)

Tuberculin skin test:

result evaluation

The amount of induration should be measured by a trained person 48~72hours after administration

Intensity:

– or ±: <5mm negative or doubtful

+ : 5~9mm suspicious

++ : 10~19mm positive

+++ : >=20mm strong-positive

++++ : blister,ulcer,lymphangitis,double rings

What does it mean: Positive result

Previous infection with TB

Previous vaccination with BCG

Active tuberculosis

<=3 year without prior vaccination

> = 15mm

conversion occurring within 2 years

What does it mean: Negative result

Not infected with TB

False-negative :

incubation period

immunosuppression or immunodeficiency

technical error or improper reagents

Diagnosis

Laboratory Study

Clinical diagnosis

History

Clinical manifestation

Tuberculin test

Roentgenographic examination: helpful

Therapeutic trial

Diagnosis

Laboratory Study

Clinical diagnosis

History

Clinical manifestation

Tuberculin test

Roentgenographic examination

Therapeutic trial: final

Prevention of TB

Avoiding contact with those with open

pulmonary tuberculosis

BCG (Bacillus Calmette-Guerin)

vaccination

Chemoprophylaxis

Prevention of TB

Avoiding contact with those with open

pulmonary tuberculosis

BCG (Bacillus Calmette-Guerin)

vaccination

Chemoprophylaxis

Tuberculosis control programs

involve case finding and treatment.

Treatment

Antituberculosis therapy:

early, dosage, combination, regular, whole course

intensification stage and consolidate stage

directly observing therapy shortcourse (DOTS)

Corticosteroids

Symptomatic management

Supportive care

Recommended treatment regime

Pediatrics

Pertussis andPertussis syndrome

Definition

Pertussis (whooping cough)

caused by Bordetella pertussis,

The pertussis syndrome

includes disease caused by Bordetella pertussis

and certain other infectious agents

Etiology

Bordetella pertussis

tiny, Gram-negative, coccobacilli

Other infectious agents

Bordetella parapertussis

Adenovirus

Dual infection (of above)

Other common pathogens of protracted cough:

mycoplasma, chlamydia, RSV, parainfluenza virus

Epidemiology

Infect only humans and transmitted person

to person by coughing

Most contagious during the earliest stage

The peak incidence <4 m

The annual rate--100 to 200/100,000, higher

in developing countries

Clinical manifestation

The mean incubation period is 6 days.

The progression of pertussis

Catarrhal stage

Paroxysmal stage

Convalescent stage

Clinical manifestation

Catarrhal stage

nonspecific signs

• Injection

• increased nasal secretions

• low-grade fever

last 1 to 2 weeks

Clinical manifestation

The paroxysmal stage

approximately 2 to 4 weeks.

as catarrhal symptoms wane, coughing begins first

as a dry, intermittent, irritative hack;

then evolve into coughing in paroxysms during

expiration, causing young children to lose their

breath (machine-gun burst of uninterrupted

coughs).

Clinical manifestation

The paroxysmal stage After the most insignificant startle from a draught,

light, sound, sucking or stretching, a well-appearing young infant begins to choke, gasp, and flail extremities, eyes watering and bulging, face reddened or purple, tongue protruding maximally until at the seeming last moment of consciousness.

Characteristic whoop follows this paroxysm of cough (the forceful inhalation against a narrowed glottis).

Others: post-tussive emesis, conjunctival hemorrages and petechiae on the upper body

Clinical manifestation

The Convalescent stage

gradual resolution of symptoms over

1 to 2 weeks.

residual cough may persist for

months, especially with physical

stress or respiratory irritants

Clinical manifestation

Young infants may not display the classic

pertussis syndrome: the first signs may be episodes of apnea

unlikely to have the classic whoop

more likely to have CNS damage as a result of

hypoxia

more likely to have secondary bacterial

pneumonia.

Laboratory studies

The diagnosis depends on isolation of B. pertussis Culture of nasopharyngeal swabs

Direct fluorescent antibody staining

Serologic tests are not useful for diagnosis of acute infection.

Leucocytosis (20,000~ 50,000/mm3) with lymphocytosis is characteristic beyond the neonatal age

Imaging study

NOT specific

Segmental lung atelectasis

not unusual during pertussis, especially during the

paroxysmal stage.

Perihilar infiltrates

common and similar to what is seen in viral

pneumonia.

Diagnosis and differential diagnosis

the diagnosis based on recognition of the

pattern of illness is quite accurate

Respiratory viruses such as RSV, parainfluenza

virus, and C. pneumoniae among infants and

M. pneumoniae in older children may produce a

bronchitic illness that is not distinguished

easily from pertussis.

Complications

Major complications:hypoxia, apnea, pneumonia,

seizures, encephalopathy, and malnutrition.

The most frequent complication is pneumonia

caused by B. pertussis itself or resulting from

secondary bacterial infection from S.

pneumoniae, Hib, and S. aureus.

Complications

Other complications

atelectasis, pneumomediastinum,

pneumothorax, or interstitial or

subcutaneous emphysema; epistaxis;

hernias; and retinal and subconjunctival

hemorrhages, otitis media and sinusitis .

Goal of therapy

Limit the number of paroxysms

Observe the severity of cough to provide

assistance when necessary

Maximize nutrition, rest, and recovery

without sequelae

Treatment

Erythromycin given early, eradicates nasopharyngeal carriage

of organisms within 3 to 4 days and ameliorates the effects of the infection.

not effective in the paroxysmal stage.

Azithromycin and clarithromycin

TMP-SMZ

Pertussis-specific immunoglobulin ( effective)

Prevention

Active immunization

acellular pertussis vaccine, given in

combination with the toxoids of tetanus

and diphtheria (DTaP with an efficacy of

70% to 90%;

Compared with older, whole cell pertussis

vaccines, acellular vaccines have fewer

adverse effects and local reactions.

Prevention

Erythromycin and other macrolides

effective in preventing disease in

contacts exposed to pertussis.

Prevention

Close contact <7y should be given a macrolide antibiotic.

should receive a booster dose of DTaP, unless a

booster dose has been given within the preceding

3 years.

Close contact > 7y prophylactic macrolide antibiotic for 10 to 14 days

NOT the vaccine.

Q&A

OR E-mail to zmchen@zju.edu.cn

Thank you for your attention