Diagnosis of Childhood Tuberculosis - medIND

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SYMPOSIUM on Tuberculosis. DIAGNOSIS OF CHILDHOOD TUBERCULOSIS. A BANG *, P CHATURVEDI**. ABSTRACT. Tuberculosis is fast gaining prime ...
SYMPOSIUM on Tuberculosis DIAGNOSIS A BANG *,

OF

CHILDHOOD

TUBERCULOSIS

P CHATURVEDI** ABSTRACT

Tuberculosis is fast gaining prime global importance due to the global HIV / AIDS pandemic and emergence of multi-drug resistant strains. The problem remains of utmost importance in the pediatric age group due to the high rate of tubercular infection in India and the impact of tuberculosis on the growth and development of the children, child mortality and morbidity. However, tuberculosis can very easily be missed as the clinical features of tuberculosis can at times be extremely vague and non-specific. Also sputum, which is the best adulthood specimen for an adequate AFB yield, is hard to obtain in children. History of contact may not always be elicited due to the fear of stigmatization. Radiological features are extremely nonspecific and Tuberculin skin tests must be interpreted with a scientific understanding of the possibilities of false positive and false negative tests. Culture yield is positive in only about a third of the patients. Other newer modalities are costly, less available and require trained personnel. Thus, absence of a single gold standard investigation necessitates a thorough understanding of the strengths and limitations of the available diagnostic modalities and a scientific and focused approach. This article gives an insight into this.

Pediatric tuberculosis poses many difficult challenges and problems as compared to the adults. Firstly, A child with its underdeveloped immune system may not present with the classical symptoms and signs of the disease. This is one of the commonest reasons for under diagnosis of pediatric tuberculosis. The disease is usually characterized by an insidious onset of extremely vague symptoms. Hence a high degree of suspicion has to be there to make an early diagnosis. Secondly, The primary complex may be totally asymptomatic in as large as 65% of the

cases.1 To avoid missing these, any child with vague symptoms and growth failure of any nature must be examined and investigated thoroughly for tuberculosis. In some cases, it may manifest as a transient illness. Most children will have a slow growth or weight gain, failure to thrive and despite seemingly adequate diet, may fall in grade 3 or 4 PEM. Tubercular toxemia presents with constitutional symptoms like mild to moderate grade fever, loss of appetite, tachycardia, progressive weight loss and night sweats. Lastly, Although a cough persisting for more than 15 days must raise the suspicion of tuberculosis, one must remember bronchial asthma and pertussis as 2 important differential diagnoses. Post measles Staphylococcal pneumonia should also be ruled out if there is a history of recent attack of measles, which must be specifically

* Lecturer, ** Prof, Department of Pediatrics, MGIMS, Sevagram, Wardha. Address for Correspondence : Dr Akash Bang, Department of Pediatrics, MGIMS, Sevagram , Wardha, MH 442102. E mail: [email protected]

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therapy. WHO has issued provisional guidelines2 (Table 1) for the diagnosis of tuberculosis to tackle these problems of under and over diagnosis.

asked for. Seasonal attacks of cough and/or wheeze, rapid improvement over days will point against the diagnosis of Primary Pulmonary Complex (PPC). PPC either improves slowly with time or worsens. It typically presents as a child with a cough, low intermittent fever for more than 2 weeks with an observed weight loss. Nasal congestion as one of the primary symptoms, very high, persistent fever point against tuberculosis. Absence of a single gold standard investigation remains the greatest hurdle in the diagnosis of tuberculosis. Sputum-the commonest specimen used for detection of the tubercular bacilli in adults - is not available readily in children. Further, the pediatric cases of pulmonary tuberculosis are usually non-cavitary and so a large proportion of cases are paucibacillary. Though gastric lavage is still better than other invasive techniques like bronco-alveolar lavage, still as it is diluted with gastric juices, its yield is quite low. Radiographic abnormalities are nonspecific in adults as well as in children. Hence, one of the commonest problematic issues in the management of pediatric tuberculosis is overdiagnosis in the hands of over enthusiastic health care workers. Common reasons for an overwhelmingly large number of over diagnosis include : - Subjectively made diagnosis - Lack of adequate diagnostic facility - Absence of sputum in the pediatric Primary Pulmonary Complex. - Inadequate training of the personnel in radiological interpretation

Table 1: WHO Provisional Guidelines for the Diagnosis of Tuberculosis 2 : 1) Suspected tuberculosis Any child with history of contact with confirmed case of pulmonary tuberculosis who  Is not gaining normal health after measles, pertussis etc.  Has loss of weight, cough and wheeze not responding to adequate antibiotic therapy for respiratory diseases.  Has painless swelling in superficial group of lymph nodes. 2) Probable tuberculosis A suspected case and any of following  Positive TST (10mm induration or more)  Suggestive radiological findings  Suggestive histopathological appearance of biopsy  Favorable response to anti tubercular therapy 3) Confirmed tuberculosis  Detection of acid fast bacilli by microscopy and culture.  Identification of acid fast bacilli as Mycobacteria by culture characteristics

The diagnostic dilemma arising out of the above pitfalls in the history, clinical examination and investigations must be solved by a consistent, scientific and rational approach to the diagnosis. 1. Radiological Diagnosis of Childhood TB Chest Roentgenogram is the basic and most widely used radiological investigation used for pulmonary tuberculosis. An ideal chest X ray is a postero-anterior view and an inspiratory film. An antero-posterior view taken for sheer convenience or an inadvertent expiratory film in

The end result is that a large number of respiratory illnesses like post measles bronchopneumonia, pertussis, viral lower respiratory tract infections, asthma etc receive anti tubercular 13

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Diagnosis of Childhood Tuberculosis

a crying and uncooperative child can be extremely misleading due to apparent mediastinal widening, increased hilar prominances, increased curvature of trachea, increased carinal angle etc, all of which can mimic mediastinal and hilar lymphadenopathy. Similarly, a malrotated film due to wrong position or an improper X ray technique may cause slight malrotation which will show increased prominence of manubrium sterni and the lateral borders of thoracic vertebrae giving a false impression of enlarged lymph nodes.

2. A chest X ray taken during the acute phase of an infective or allergic disease may show various false signs like increased pulmonary vascular and interstitial markings in bronchial asthma or eosinophilia or enlarged hilar lymph nodes in bacterial or viral lower respiratory tract infections or wheezy bronchitis. These should disappear after antibiotics or appropriate therapy for about 2-4 weeks. However 4 to 6 weeks may be needed for complete resolution of these non tubercular lesions.

Common findings in the chest X ray include : i ) The primary pulmonary complex (PPC) may be seen as nodal and/or parenchymal lesions. It may also show signs of pleural involvement.

3. Clues towards tubercular etiology which at times may justify immediate institution of anti tubercular therapy include i ) Parenchymal lesions accompanying a clearcut mediastinal adenopathy. ii) A clearcut consolidation with a collapse is usually tubercular in etiology rather than pyogenic. However foreign body inhalation has to be excluded.

ii) Post Primary Lesion may include calcification and fibrosis of the nodal and parenchymal lesions of PPC. iii) Progressive primary lesion includes consolidation and/or collapse, cavity, significant pleural involvement, bronchopneumonia etc.

4. Common misleading features on a chest X ray : i ) A wet minor fissure may be confused with a primary pulmonary complex. ii) Thymic shadow should not be mistaken for a mediastinal adenopathy. iii) Subcarinal widening may not necessarily be due to subcarinal lymph node enlargement. Other signs of left atrial enlargement must be looked for clinically, in ECG and in the X ray. iv) Other etiologies of lymph node enlargement like lymphomas must be kept in mind. v) Bronchopneumonia may present a picture of miliary tuberculosis.

iv) Miliary tuberculosis may present with the typical miliary mottling. Other uses of radiological modalities include CT scan, USG, MRI etc which can be used for detection of mediastinal or intraabdominal lymph nodes, serous effusions, as a guide during fine needle aspiration of the lymph nodes. The characteristic feature of a single small ring enhancing lesion can be sometimes seen on contrast CT scan in cases of neurotuberculosis. Things to remember regarding radiological diagnosis of tuberculosis : 1 . A proven PPC may have a normal chest X ray in as large as 15 % patients.3

5. The single small ring enhancing CT lesions on contrast CT scan may also be present in cases of neurocysticercosis besides 14 J MGIMS, March 2008, Vol 13, No (i), 12 - 19

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tuberculoma. For this differentiation, the other features, as suggested by Rajshekhar et al4 are given in Table 2.

injected over the volar surface of forearm, in the long axis of the forearm. 

The needle used should be a 26 or 27G steel or platinum needle with a glass or a plastic tuberculin syringe.



If the technique of administration is right, there should be formation of a wheel of about 6-10mm which can be used to cross check the correctness of the method.



The injection site should not be rubbed.

Table 2 : Differences between Neurocysticercosis and Tuberculoma4 : Features on CT scan

Neurocysticercosis

Tuberculoma

1. Size

< 20mm

> 20mm

2. Shape / outline

Regular in most

Irregular

3. Mass effect / midline shift

NIL

+ in most

4. Scolex

+

Absent

5. Calcification

Nodular calcified mass

Target sign +

Results : TST should be read after 48 to 72hrs in a proper illumination. The forearm is slightly flexed at the elbow. The induration should be read and not the erythema. This differentiation can be done by simple palpation or the "Pen method.8" In this, a ball point pen is used to draw a line from one side of the induration till the pen point stops due to the slight resistance offered by the elevated edge of the induration. This is then repeated on the other side of the induration. Now, the diameter of induration is measured between the opposing end points of these two lines, so that it is measured transversely to the long axis of the forearm. The reading is recorded in millimeters.

2. Immunological Diagnosis of Childhood TB A. Tuberculin Skin Test (TST) : TST tests the sensitivity of an individual to the Tuberculin antigen and if positive, indicates a prior infection or exposure to Mycobacterium tuberculosis. Usually it takes 3-6 weeks to become positive after acquiring the infection. However, rarely a longer period of as long as 3 months has also been described.5 Techniques : The two commonly employed techniques include intracutaneous Mantoux Test (Mx) and percutaneous multiple puncture skin test (Heaf). Though Heaf test is easier to administer on a mass basis, its results can not be used for diagnostic purposes. Thus if the purpose of the testing is a diagnostic one, Mantoux test does need to be administered after Heaf test.6 The most commonly used technique of TST in India is the Mantoux test and is used almost synonymously with TST.

Interpretation : In Indian setting as suggested by Udani 9 et al and IAP, the following working definitions are taken for the TST interpretation:

Procedure6,7:  An intra-dermal injection of 0.1 ml (1TU) of PPD RT23 in TWEEN 80 is



Positive

:> 10mm induration



Negative

:< 5mm induration



Borderline :5-9mm induration

The last two categories may be considered as a positive if the patient has had recent contact 15 J MGIMS, March 2008, Vol 13, No (i), 12 - 19

Diagnosis of Childhood Tuberculosis

3. Booster effect due to repeated or sequential TST 4. Errors in administrating the test Subcutaneous injection 5. Errors in reading

with infectious tuberculosis disease or his clinical features are consistent with HIV infection or immuno suppression due to some other cause. False negative TST10: Any condition that leads to compromised cell mediated immunity will cause a false negative TST. The causes are given in Table 3.

B. BCG Test : Some children who don't react to a standard TST with 1-2 TU PPD with TWEEN 80 do react to BCG standard dose (5-10 TU). The reason for this phenomenon is not well understood and is thought to be due to the larger antigen dose in BCG. Thus BCG test is more sensitive but less specific. The test is done directly without prior TST or when TST is negative and is read on the third day. The characteristics of how the normal and various types of positive BCG reactions proceed are given in the Table 4. The induration seen during the classical positive reaction i.e. a positive BCG test is further graded as follows -

Table 3 : Causes of false negative TST10 : 1. Related to the subject-

2. Related to the testing-

a) Infections : ΠViral- measles, varicella, HIV ΠBacterialoverwhelming TB ΠLive virus immunisation

a) Tuberculin ΠChemical denaturation, ΠAdsorption, ΠWrong dilution, ΠImproper storage.

b) Metabolic diseases : ΠChronic Renal Failure c) P E M d) Malignancies : ΠLeukemia ΠLymphomas e) Immunosuppression: ΠDrugs ΠLymphoreticular disorders f ) Age : Newborns g) Stress: ΠBurns ΠSurgery, ΠGVHD

b) Administration ΠSubdermal, ΠToolittle injected

1+ if 5 -9 mm, 2+ if 10 -20 mm, 3+ if 21- 30 mm.

c) Readings ΠInexperienced reader, ΠBias

Table 4 : BCG Reactions : Type of Reaction to the BCG test

d) Error in recording

Approx time required for development of Induration Pustule Healing / Papule scab

1. Normal 2 wks 4-6 wks 7-10 wks 2. Classical positive 24-72 hrs 5-8 days 10-15 days 3. Accelerated positive Few hrs Day 3 5-6 days 4. Delayed positive 3 days Behaves like classical positive

False positive TST : The various reasons of a falsely positive TST are as follows -

C. Interferon Gamma assays : QuantiFERON-TB (QFT) assay is an in-vitro assay, which measures the gamma interferon released by the host cells in the whole blood in response to the stimulation

1 . Infection with nontuberculous or atypical mycobacteria. 2. Recent vaccination with BCG 16

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by the purified protein derivative during the TST.

Drawbacks  30% of the patients may fail to produce antibodies in sufficiently high titres that can be easily detected.  Antibodies when interpreted alone are not able to differentiate between past and recent disease.  Sensitivity of serodiagnosis is poor.

Advantages14 :  Its results are comparable to the TST results.  The results are less affected by BCG vaccination.  This test can also differentiate the responses due to tubercular and atypical Mycobacteria.  It also avoids the inter observer variability and subjectivity introduced in the TST due to different techniques of administration and reading.

Advantages  More speedy method,  No need of collection of specimens from the diseased site. E. Adenosine Deaminase (ADA) activity : Increased levels of ADA are found in tuberculosis in various body fluids like pleural, peritoneal, pericardial fluids and sera. Recent studies show that CSF ADA activity is also increased in tubercular meningitis.11 Simultaneous estimation of serum and CSF ADA has an added advantage to differentiate between tuberculous and pyogenic meningitis.12 A recent prospective clinical trial by Kayacan et al13 for the diagnostic value of ADA in the bronchoalveolar lavage claims a sensitivity of 100% and a specificity of 85.3%. The advantages over sputum PCR are that the ADA reports are ready within a couple of hours vis-à-vis a couple of days required for the PCR reports. The cost is also cheaper than the PCR.

D. Sevodiagnosis : Like CMI, the antibody mediated immune response of the host to various Mycobacterial antigens can also be measured. The most commonly employed technique is Enzyme Linked Immuno Sorbent Assay-ELISA- to detect antibodies to various purified or complex antigens. Amongst the various antibodies detected, it must be remembered that the antibodies IgG, IgM and IgA are absent in healthy individuals. IgM is the first one observed after contact and IgM in CSF is useful for diagnosis of tubercular meningitis. Table 5 summarizes the diagnostic value of various antibodies. Table 5 : Diagnostic approach to the serodiagnosis : IgM IgG IgA TST -

-

-

+

History of Contact +

Interpretation no disease

+

-

-

+/-

+/-

recent infection

-

+

+/-

+

+

good immunity

+

+

+/-

+

re-exposure

consider

+

disease

3. Microbiological Diagnosis of Childhood TB: A) Z N Staining & Special stainings : Besides the conventional Zeil Nelson stain, the acid fast tubercular bacilli can be directly visualized after staining with various stains like Flurochrome, Auramine-O, Rodamine-O etc. The specimens used can be a sputum sample if generated and expectorated. 17 J MGIMS, March 2008, Vol 13, No (i), 12 - 19

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period of 9 to 14 days, the growth positivity increases to 95%.16 Various other culture systems include Septicheck AFB System which shows growth within 3 weeks, Mycobacterial Growth Indicator Tube System (MGIT) etc. However, it must be remembered that most studies show that in children, the culture positive confirmation rates are quite low- 30 to 50%.5

Otherwise the commonest specimen used in pediatric practice is an early morning gastric aspirate, repeated for 3 consecutive days to increase the probability of the yield. If the sputum is hard to obtain, another method that is popularizing is a Fibreoptic Bronchoscopy with Bronchoalveolar Lavage (BAL). The lavage can then be searched for the acid fast bacilli. However recent studies15 suggest that the yields of BAL are at the most only equivalent with gastric aspirate. Further gastric lavage is much less invasive than BAL. Hence workers suggest that following are the indications to which bronchoscopy and BAL should be restricted: 



4. Molecular Dignosis of Childhood TB A) Demonstration of various antigens of Mycobacterium tuberculosis : Some of the newer techniques also detect the various Mycobacterial antigens themselves. Specific antigens, which can be detected, are - lipro arabinomannon, 38kDa Ag etc. Various other antigens that are useful in childhood tuberculosis include Ag 85 complex, 75kDa Ag etc.

As a therapeutic or diagnostic procedure to determine the extent of the endobronchial disease or bronchial obstruction. To evaluate the potential for bronchiectasis or bronchial stenosis.

B) Polymerase Chain Reaction (PCR) The use of PCR is restricted to the following situations because of the prohibitive cost, and the highly trained personnel it needs :  Identifying DNA of Mycobacterium tuberculosis from those clinical specimens, which are negative by microscopy.  Other situations with a negative microscopy like significant pulmonary disease, HIV etc  To detect whether the acid fast bacilli seen in microscopy are typical or atypical.  To detect various genetic modifications associated with drug resistance.

B) Cultures : The acid fast tubercular bacilli can also be grown in culture media like the conventional LJ medium and a host of other media like Petragnani, American Thoracic Society, Middle Brook TH10 Medium, TH11 Medium. All of these more or less take around 7 to 10 weeks to grow the bacilli. A recent development includes a newer medium called BACTEC medium where a C14 labeled Palmitic acid is used in the preparation of the medium. When the growing Mycobacterium tuberculosis liberates CO2, the liberation of the 14CO2 labeled with the C14 is measured by the medium. The result is reported as a "Growth Index". This is a much rapid method than the conventional culture media and within a

Summary : ™ Various respiratory illnesses in children can mimic tuberculosis. ™ History of contact with tuberculosis, persistent cough, failure to gain weight 18 J MGIMS, March 2008, Vol 13, No (i), 12 - 19

A Bang, P Chaturvedi

pen method compared to traditional palpation. Chest 1987, 92:234-236.

should arouse a high degree of suspicion for tuberculosis. ™

TST may not always be positive due to various reasons.

™

A non-resolving radiological lesion must arouse a high suspicion of tuberculosis.

™

9. Udani PM, Somu N. Tuberculosis in children : Clinical features and presentation. In: Childhood Tuberculosis. Lupin Publications, 1996;18-20. 10. Rajajee S. Tuberculin and BCG tests. Indian J Pediatr 2000(Suppl);67:S9-S13. 11. Malan C, Donald PR, Golden M, Taljaard JJF. Adenosine deaminase levels in cerebrospinal fluid in the diagnosis of tubercular meningitis. J Trop Med Hyg 1984;87:33-40.

Isolation of AFB is only possible in 30% cases from gastric lavage and other body fluids.

™

Other sero-diagnostic modalities have limitations,arecostlierandnotesilyavailable.

™

High index of clinical suspicion with a properly focused approach as per the guidelines given in the article will help in solving the problem of over - and under - diagnosis.

12. Chaturvedi P, Vaidya J, Harinath B, Pramanick B. Adenosine deaminase levels in cerebrospinal fluid and serum in the diagnosis of tubercular meningitis. Jr Trop Pediatr 2000;46:378-379. 13. Kayacan O, Karnak D, Delibalta M, Beder S, Karaca L, Tutkak H. Adenosine deaminase activity in bronchoalveolar lavage in Turkish patients with smear negative tuberculosis. Respir Med 2002 Jul;96(7):536-541. 14. Mazurek GH, LoBue PA, Daley CL, Bernardo J, Lardizabal AA, Bishai WR et al. Comparison of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA 2001;286:1740-1747.

References : 1.

Agrons GA, Markowitz RI, Kramer SS. Pulmonary tuberculosis in children. Semin Roentgenol 1993,28:158-172

15. Abadco DL, Steiner P. Gastric lavage is better than bronchoalveolar lavage for isolation of Mycobacterium tuberculosis in childhood pulmonary tuberculosis. Pediatr Infect Dis J 1992;11:735-738.

2. Singh D, Gupte S. Pediatric pulmonology. In : Gupte S (ed) The Short Textbook of Pediatrics, 10th edn. New Delhi : Jaypee Brothers, 2004;247-279. 3. Miller WT, Miller WT Jr. Tuberculosis in the normal host: Radiologic findings. Semin Roentgenol 1993, 28:109-118

16. Venkataraman P, Herbert D, Paramasivan CR, et al. Evaluation of the BACTEC radiometric method in the early diagnosis of tuberculosis. Indian J Med Res 1998;108:120-127.

4. Rajshekhar V, Haran RP, Prakash SG, Chandy MJ. Differentiating solitary small cysticercous granulomas and tuberculomas in patients with epilepsy : clinical and computed tomographic criteria. J Neurosurg 1993;78(3):402-407.

17. Albert H, Heydenrych A, Brookes R, Mole RJ, Harley B, Subotsky E et al. Performance of a rapid phage-based test, FASTPlaque TB, to diagnose pulmonary tuberculosis from sputum specimens in South Africa. Int J Tuberc Lung Dis 2002 Jun;6(6):529-537.

5. Jacobs RF, Starke JR. Tuberculosis in children. Med Clin North Am 1993,77:1335-1357. 6. Committee on infectious diseases. Screening for tuberculosis in infants and children. Pediatrics 1994,93:131-134. 7.

18. Cooksey RC, Crawford JT, Jacobs WR Jr, Shinnick TM. A rapid method for screening antimicrobial agents for activities against a strain of Mycobacterium tuberculosis expressing firefly luciferase. Antimicrob Agents Chemother 1993;37:1348-1352.

American Thoracic Society. The Tuberculin skin test - Official ATS statement. Am Rev Respir Dis 1984,124:356-363.

19. Cantwell MR, Shehab ZM, Costello AM, et al. Brief report : Congenital Tuberculosis. N Engl J Med 1994,330: 1051-54.

8. Jordan TJ, Sunderam G, Thomas L, Reichman LB. Tuberculin reaction size measurement by the

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