Tuberculosis laboratory findings: Difference between revisions

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{{Tuberculosis}}
{{Tuberculosis}}
{{CMG}}; {{AE}} {{AL}}
{{CMG}}; {{AE}} {{Mashal Awais}}; {{AL}}
 
==Overview==
Routine laboratory exams are usually normal. The presence of [[acid-fast-bacilli]] (AFB) on a [[sputum]] smear or another specimen usually indicates TB disease and a positive culture for [[M. tuberculosis]] confirms the diagnosis. Other examples of laboratory tests are [[urinalysis]], [[peritoneal fluid]], or [[CSF]] analysis and [[Interferon-Gamma release assays]] ([[Interferon-γ release assays|IGRA]]).


==Laboratory Findings==
==Laboratory Findings==
===Mantoux Tuberculin Skin Test===
Routine laboratory tests are usually normal. In some patients, the subsequent abnormalities could also be found:
The Mantoux tuberculin skin test (TST) is the standard method of determining whether a person is infected with Mycobacterium tuberculosis. Reliable administration and reading of the TST requires standardization of procedures, training, supervision, and practice.
The TST is performed by injecting 0.1 ml of tuberculin purified protein derivative (PPD) into the inner surface of the forearm.  The injection should be made with a tuberculin syringe, with the needle bevel facing upward.  The TST is an intradermal injection.  When placed correctly, the injection should produce a pale elevation of the skin (a wheal) 6 to 10 mm in diameter.


The skin test reaction should be read between 48 and 72 hours after administration. A patient who does not return within 72 hours will need to be rescheduled for another skin test.
*Mild normocytic [[anemia]] can be present in almost half of patients.
*Increased [[erythrocyte sedimentation rate]] (ESR)
*Mild [[leukocytosis]]
*[[Hyponatremia]]
*[[Hypercalcemia]]
*Elevated [[alkaline phosphatase]] levels
*Mild elevation of [[liver enzymes]]
*Findings of [[adrenal insufficiency]] in case of [[adrenal gland]] involvement (low [[cortisol]] and [[aldosterone]] levels)


The reaction should be measured in millimeters of the induration (palpable, raised, hardened area or swelling). The reader should not measure erythema (redness). The diameter of the indurated area should be measured across the forearm (perpendicular to the long axis).
===Acid-Fast Bacilli===
<div style="float:right">
[[Image:Acid Fast Bacilli Sputum.JPG|thumb|200px|Acid-fast-bacilli in sputum smear]]
</div>


Presence of [[acid-fast-bacilli]] (AFB) on sputum smear or on another specimen usually indicates TB disease.  Although [[acid-fast microscopy]] is easy and quick, it does not confirm a [[diagnosis]] of [[Tuberculosis]] as some [[acid-fast-bacilli]] are not [[M. tuberculosis]]. Consequently, a culture is done on all initial samples for confirmation of the diagnosis.


====Classification of Tuberculin Reaction <ref>{{cite web|url= http://www.cdc.gov/tb/publications/factsheets/testing/skintesting.htm|title= CDC Tuberculin Skin Testing| }}</ref>====
Sputum smears and [[microbiological culture|cultures]] should be performed to detect [[acid-fast bacilli]] if the patient is producing [[sputum]]. The best method for this is [[fluorescence microscopy]] ([[auramine-rhodamine stain]]ing), which is more sensitive than conventional [[Ziehl-Neelsen stain]]ing.<ref>{{cite journal | author=Steingart K, Henry M, Ng V, ''et al.'' | title=Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review | journal=Lancet Infect Dis | year=2006 | volume=6 | issue=9 | pages=570&ndash;81 | doi=10.1016/S1473-3099(06)70578-3 }}</ref>
{|
[[File:Mantoux tuberculin skin test.jpg|thumb|200px|right|Image from Public Health Image Library (PHIL)]]
[[File:Mantoux test.jpg|thumb|200px|right|Image from Public Health Image Library (PHIL)]]
|}
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Tuberculin Rection}}
! style="background: #4479BA; width: 450px;" | {{fontcolor|#FFF|Considered a Positive Result in:}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''≥ 5 mm '''
| style="padding: 5px 5px; background: #F5F5F5;" | 
*HIV-positive person
*Recent contacts of TB case
*Persons with nodular or fibrotic changes on CXR consistent with old healed TB
*Patients with organ transplants and other immunosuppressed patients
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''≥ 10 mm  '''
| style="padding: 5px 5px; background: #F5F5F5;" |
*Recent arrivals (less than 5 years) from high-prevalent countries
*Injection drug users
*Residents and employees of high-risk congregate settings (e.g., prisons, nursing homes, hospitals, homeless shelters)
*Mycobacteriology lab personnel
*Persons with clinical conditions that place them at high risk (e.g., [[diabetes]], prolonged [[corticosteroid|corticosteroid therapy]], [[leukemia]], [[end-stage renal disease]], [[malabsorption|chronic malabsorption syndromes]], low body weight)
*Children less than 4 years of age, or children and adolescents exposed to adults in high-risk categories
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''≥ 15 mm '''
| style="padding: 5px 5px; background: #F5F5F5;" |
*Persons with no known risk factors for TB
|-
|}


In case of inability of sufficient [[sputum]] production, specimens can be obtained by inducing sputum, gastric washings, a [[laryngeal swab]], [[bronchoscopy]] with bronchoalveolar lavage, or [[fine-needle aspiration]] of a collection. A comparative study reported that inducing three [[sputum]] samples is more [[sensitivity (tests)|sensitive]] than three gastric washings.<ref name="pmid17479935">{{cite journal |author=Brown M, Varia H, Bassett P, Davidson RN, Wall R, Pasvol G |title=Prospective study of sputum induction, gastric washing, and bronchoalveolar lavage for the diagnosis of pulmonary tuberculosis in patients who are unable to expectorate |journal=Clin Infect Dis|volume=44 |issue=11 |pages=1415-20 |year=2007 |pmid=17479935 |doi=10.1086/516782}}</ref>


====BCG Vaccine and Tuberculin Skin Test====
Other [[Mycobacterium|mycobacteria]] are also [[acid-fast]]. If the smear is positive, [[PCR]] or gene probe testing can differentiate ''[[Mycobacterium tuberculosis|M. tuberculosis]]'' from other mycobacteria. Even if sputum smear is negative, [[tuberculosis]] cannot be excluded without obtaining negative [[cultures]].


There is disagreement on the use of the Mantoux test on people who have been immunized with BCG. The US recommendation is that in administering and interpreting the Mantoux test, previous BCG vaccination should be ignored; the UK recommendation is that [[interferon-γ release assays|interferon-γ tests]] should be used to help interpret positive tuberculin tests, also, the UK do not recommend serial tuberculin skin testing in people who have had BCG (a key part of the US strategy). In their guidelines on the use of [[QuantiFERON Gold]] the US Centers for Disease Control and Prevention state that whereas Quantiferon Gold is not affected by BCG inoculation tuberculin tests can be affected.<ref>CDC - [http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium tuberculosis Infection, United States]</ref>  In general the US approach is likely to result in more false positives and more unnecessary treatment with potentially toxic drugs; the UK approach is as sensitive in theory and should also be more specific, because of the use of interferon-γ tests.
===Culture===
A positive [[Culture medium|culture]] for [[Mycobacterium tuberculosis|M. tuberculosis]] confirms the diagnosis of TB disease. [[Culture medium|Culture]] examinations are crucial and should be done on all [[specimens]], regardless of [[AFB smear]] results. Laboratories are necessary to report positive results on smears and [[cultures]] within 24 hours by telephone or fax to the primary health care provider and to the state or local [[Tuberculosis|TB]] control program, as needed by law.  


Under the US recommendations, latent TB infection (LTBI) diagnosis and treatment for LTBI is considered for any BCG-vaccinated person whose skin test is 10 mm or greater, if any of these circumstances are present:
Many types of [[cultures]] are available for [[Mycobacterium tuberculosis|M. tuberculosis]], including [[Löwenstein-Jensen]] (LJ), [[Kirchner]], or Middlebrook media. <ref name="pmid12614730">{{cite journal |author=Drobniewski F, Caws M, Gibson A, Young D |title=Modern laboratory diagnosis of tuberculosis |journal=Lancet Infect Dis |volume=3 |issue=3 |pages=141-7 |year=2003 |id=PMID 12614730}}</ref>. [[Culture medium|Culture]] of [[Mycobacterium|Mycobacteria]] often takes 4--8 weeks to grow and can help distinguish from several types of [[Mycobacterium|mycobacteria]]. Other kinds of [[Culture medium|culture]] are available, this include automated systems in which the [[Mycobacterium|mycobacteria]] grow at a faster rate. [[MB/BacT]], BACTEC 9000, as well as the [[Mycobacterial Growth Indicator Tube]] (MGIT).  The microscopic-observation drug-susceptibility (MODS) culture is considered a faster and more accurate method <ref name="pmid17035648">{{cite journal |author=Moore D, Evans C, Gilman R, Caviedes L, Coronel J, Vivar A, Sanchez E, Piñedo Y, Saravia J, Salazar C, Oberhelman R, Hollm-Delgado M, LaChira D, Escombe A, Friedland J |title=Microscopic-observation drug-susceptibility assay for the diagnosis of TB |journal=N Engl J Med |volume=355 |issue=15 |pages=1539-50 |year=2006 |id=PMID 17035648}}</ref><ref name="MinionLeung2010">{{cite journal|last1=Minion|first1=Jessica|last2=Leung|first2=Erika|last3=Menzies|first3=Dick|last4=Pai|first4=Madhukar|title=Microscopic-observation drug susceptibility and thin layer agar assays for the detection of drug resistant tuberculosis: a systematic review and meta-analysis|journal=The Lancet Infectious Diseases|volume=10|issue=10|year=2010|pages=688–698|issn=14733099|doi=10.1016/S1473-3099(10)70165-1}}</ref>.
*Was in contact with another person with infectious TB
*Was born or has resided in a high TB prevalence country
*Is continually exposed to populations where TB prevalence is high.


===Microbiological Studies===
{|
A definitive diagnosis of tuberculosis can only be made by culturing ''[[Mycobacterium tuberculosis]]'' organisms from a specimen taken from the patient (most often sputum, but may also include pus, [[CSF]], biopsied tissue, etc).  A diagnosis made other than by culture may only be classified as probable or presumed.
|[[Image:TB_Culture.JPG|thumb|300px|Culture: Distinctive clusters of colorless ''[[Mycobacterium tuberculosis]]'' ]]
[[Image:TB_Culture.JPG|left|thumb|Distinctive clusters of colorless ''[[Mycobacterium tuberculosis]]'' form in this culture.]]
|[[Image:Löwenstein–Jensen medium.JPG|thumb|200px|Löwenstein-Jensen media with ''[[Mycobacterium tuberculosis]]'' ]]
|}


Sputum smears and [[microbiological culture|cultures]] should be done for acid-fast bacilli if the patient is producing sputum.  The preferred method for this is [[fluorescence microscopy]] ([[auramine-rhodamine stain]]ing), which is more sensitive than conventional [[Ziehl-Neelsen stain]]ing.<ref>{{cite journal | author=Steingart K, Henry M, Ng V, ''et al.'' | title=Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review | journal=Lancet Infect Dis | year=2006 | volume=6 | issue=9 | pages=570&ndash;81 | doi=10.1016/S1473-3099(06)70578-3 }}</ref>
A sample of [[pleural]] [[exudate]] should be analyzed by [[cytopathology]] or at a cell count lab.  Samples are often [[lymphocyte]] predominant, and cytopathology is more accurate than cell count labs at detecting lymph.  If there is more [[fluid]] present, then an [[Acid-fast|AFB]] lab is more appropriate.  Sometimes, a [[pleural]] [[exudate]] lab test find [[Sterile pyuria differential diagnosis|sterile]] [[pyuria]] (particularly in [[HIV]] positive patients), but overall this finding is fairly uncommon.
Most [[extra-pulmonary TB]] is [[paucibacillary]], hence the yield of tests is very low, and a negative [[test]] result does not exclude  [[tuberculosis]] [[infection]].


If no sputum is being produced, specimens can be obtained by inducing sputum, [[gastric washing]]s, a laryngeal swab, [[bronchoscopy]] with bronchoalveolar lavage, or fine needle aspiration of a collection. A comparative study found that inducing three sputum samples is more [[sensitivity (tests)|sensitive]] than three gastric washings.<ref name="pmid17479935">{{cite journal |author=Brown M, Varia H, Bassett P, Davidson RN, Wall R, Pasvol G |title=Prospective study of sputum induction, gastric washing, and bronchoalveolar lavage for the diagnosis of pulmonary tuberculosis in patients who are unable to expectorate |journal=Clin Infect Dis|volume=44 |issue=11 |pages=1415-20 |year=2007 |pmid=17479935 |doi=10.1086/516782}}</ref>
===Drug Resistance===
For all patients, the initial ''[[M. tuberculosis]]'' isolate should be tested for [[drug resistance]]. It is necessary to identify drug resistance as early as possible to ensure effective treatment. Drug susceptibility testing has to be repeated for patients who do not respond adequately to treatment or who have positive culture results despite 3 months of therapy. Susceptibility results from laboratories have to be reported to the primary [[health care provider]] and the state or local [[Tuberculosis|TB]] control programs.


Other mycobacteria are also acid-fast. If the smear is positive, [[PCR]] or gene probe tests can distinguish ''M. tuberculosis'' from other mycobacteria. Even if sputum smear is negative, tuberculosis must be considered and is only excluded after negative cultures.
===Fluid Analysis===


Many types of cultures are available <ref name="pmid12614730">{{cite journal |author=Drobniewski F, Caws M, Gibson A, Young D |title=Modern laboratory diagnosis of tuberculosis |journal=Lancet Infect Dis |volume=3 |issue=3 |pages=141-7 |year=2003 |id=PMID 12614730}}</REF>. Traditionally, cultures have used the Löwenstein-Jensen (LJ), Kirchner, or Middlebrook media (7H9, 7H10, and 7H11). A culture of the AFB can distinguish the various forms of mycobacteria, although results from this may take four to eight weeks for a conclusive answer. New automated systems that are faster include the MB/BacT, BACTEC 9000, and the Mycobacterial Growth Indicator Tube (MGIT). The MODS culture may be a faster and more accurate method <REF NAME="pmid17035648">{{cite journal |author=Moore D, Evans C, Gilman R, Caviedes L, Coronel J, Vivar A, Sanchez E, Piñedo Y, Saravia J, Salazar C, Oberhelman R, Hollm-Delgado M, LaChira D, Escombe A, Friedland J |title=Microscopic-observation drug-susceptibility assay for the diagnosis of TB |journal=N Engl J Med |volume=355 |issue=15 |pages=1539-50 |year=2006 |id=PMID 17035648}}</REF>.
*[[Peritoneal Fluid]]:  [[Leukocyte]] count: 150-4000 mm³, [[Lymphocyte|lymphocytic]] [[pleocytosis]], [[protein]] > 3.0 g/dL, and increased [[Lactate dehydrogenase|LDH]].
*[[Cerebrospinal Fluid|Cerebrospinal fluid]]: High [[protein]], low glucose, high number of [[Lymphocyte|lymphocytes]], and elevated [[Lactate dehydrogenase|LDH]] level


*Diagnostic Microbiology ([[sputum]]): The presence of [[acid-fast-bacilli]] (AFB) on a [[sputum]] smear or other specimen often indicates TB disease (at least 10,000c is needed on the smear to get a postive  acid fast bacilli (AFB) stain).  Acid-fast [[microscopy]] is easy and quick, but it does not confirm a diagnosis of TB because some acid-fast-bacilli are not ''M. tuberculosis''. Therefore, a culture is done on all initial samples to confirm the diagnosis. However, a positive culture is not always necessary to begin or continue [[treatment]] for TB because cultures can take up to 3 weeks to yield definite results. A positive culture for ''M. tuberculosis'' confirms the diagnosis of TB disease. Culture examinations should be completed on all specimens, regardless of AFB smear results. Laboratories should report positive results on smears and cultures within 24 hours by telephone or fax to the primary health care provider and to the state or local TB control program, as required by law.  A mycobacterium tuberculosis direct test (MTD) of [[nucleic acid]] amplification can also be performed to diagnose TB.  An MTD test is similar to a [[polymerase chain reaction]] (pcr) and is very specific.  The test is more sensitive than a smear but it is less senstive than a culture, and has the benefit of same day results.
===Urinalysis===


*Diagnostic Microbiology ([[pleural fluid]]): A sample of [[pleural]] [[exudate]] can be analyzed by [[cytopathology]] or at a cell count lab.  Samples are usually [[lymphocyte]] predominant, and cytopathology is more accurate than cell count labs at detecting lymphs.  If there is more fluid present, then an AFB lab is more appropriate.  A pleural exudate lab test may find sterile [[pyuria]] (especially in [[HIV]] positive patients), but overall this finding is fairly uncommon.
*Regarding [[Kidney|renal]] [[tuberculosis]], the classic laboratory finding is [[Sterile pyuria differential diagnosis|sterile pyuria]] with [[microscopic hematuria]].
:Note: Most extra-pulmonary TB is pauci-bacillary, so the yield of tests is very low. This means that negative cultures do not mean no disease (e.g. negative [[cerebrospinal fluid]] AFB or even MTD is not that sensitive).


===Heaf Test===
===Interferon-Gamma Release Assays (IGRAs)===
[[Interferon-Gamma Release Assays]] ([[Interferon-γ release assays|IGRAs]]) are whole-[[blood]] tests that aids in diagnosing [[Mycobacterium tuberculosis]] infection, but they do not differentiate latent tuberculosis infection (LTBI) from tuberculosis disease. Two IGRAs tests that are approved by the U.S. [[Food and Drug Administration]] ([[FDA]]) and commercially available in the U.S include the [[QuantiFERON-TB Gold|QuantiFERON]]®-TB Gold In-Tube test (QFT-GIT) and the T-SPOT®.TB test ([[T-Spot]]).


The Heaf test is a [[diagnosis|diagnostic]] skin test performed in order to determine whether or not a child has been exposed to [[tuberculosis]]. Patients who exhibit a negative reaction to the test may be offered [[Bacillus Calmette-Guérin|BCG]] vaccination. The test is named after [[F. R. G. Heaf]].
[[Interferon-γ release assays|IGRAs]] measure a person’s [[immune reactivity]] to [[Mycobacterium tuberculosis|M. tuberculosis]] [[Antigenic|antigen]]. [[White blood cells]] from most individuals that have been [[infected]] with [[Mycobacterium tuberculosis|M. tuberculosis]] will produce [[interferon-gamma]] (IFN-g) when mixed with [[antigens]] (substances that can produce an [[immune]] response) derived from M. tuberculosis.


Until 2005, the test was used in the United Kingdom to determine if the [[Bacillus Calmette-Guérin|BCG]] vaccine was needed; the [[Mantoux test]] is now used instead.  The Heaf test was preferred in the UK, because it was felt that the Heaf test was easier to interpret, with less inter-observer variability, and that less training was required to administer and to read the test.  The test was withdrawn because manufacturers could not be found for tuberculin or for Heaf guns.
To do this [[test]], fresh [[blood samples]] should be mixed with [[Antigen|antigens]] and controls.  The [[Antigen|antigens]], testing methods, and interpretation [[criteria]] for [[Interferon-γ release assays|IGRAs]] are different.


The Heaf test may be informally referred to as the six pricks, as it gives six individual injections.
{| style="border: 0px; font-size: 90%; margin: 3px; width:700px" align="center"
|+'''Differences in Currently Available IGRAs'''
! style="background: #4479BA; width: 150px;" |{{fontcolor|#FFF|}}
! style="background: #4479BA; width: 300px;" |{{fontcolor|#FFF|QuantiFERON}}
! style="background: #4479BA; width: 300px;" |{{fontcolor|#FFF|T-SPOT}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" |Initial Process
| style="padding: 5px 5px; background: #F5F5F5;" |Process whole blood in 16 hours
| style="padding: 5px 5px; background: #F5F5F5;" |Process peripheral blood mononuclear cells (PBMCs) within 8 hours, or if T-Cell Xtend® is used, within 30 hours
|-
| style="padding: 5px 5px; background: #DCDCDC;" |M. tuberculosis Antigen
| style="padding: 5px 5px; background: #F5F5F5;" |Single mixture of synthetic peptides representing ESAT-6, CFP-10 & TB7.7.
| style="padding: 5px 5px; background: #F5F5F5;" |Separate mixtures of synthetic peptides representing ESAT-6 & CFP-10
|-
| style="padding: 5px 5px; background: #DCDCDC;" |Measurement
| style="padding: 5px 5px; background: #F5F5F5;" |Interferon-γ concentration
| style="padding: 5px 5px; background: #F5F5F5;" |Number of IFN-g producing cells (spots)
|-
| style="padding: 5px 5px; background: #DCDCDC;" |Possible Results
| style="padding: 5px 5px; background: #F5F5F5;" |Positive, negative, indeterminate
| style="padding: 5px 5px; background: #F5F5F5;" |Positive, negative, indeterminate, borderline
|-
| colspan="2" style="padding: 5px 5px; background: #F5F5F5;" ; |<SMALL>Table adapted from CDC <ref name="CDC TST">{{cite web|url= http://www.cdc.gov/tb/publications/factsheets/testing/IGRA.htm|title= CDC Interferon-Gamma Release Assays (IGRAs) - Blood Tests for TB Infection }}</ref></SMALL>
|-
|}


====Procedure====
{| style="border: 0px; font-size: 90%; margin: 3px; width:700px" align="center"
A Heaf gun is used to inject multiple samples of testing serum under the skin at once. A Heaf gun with disposable single-use heads is recommended. 
|+'''Advantages and Disadvantages of IGRAs'''
! style="background: #4479BA; width: 375px;" |{{fontcolor|#FFF|Advantages}}
! style="background: #4479BA; width: 375px;" |{{fontcolor|#FFF|Disadvantages}}
|-
| style="padding: 5px 5px; background: #F5F5F5;" |
*It requires a single patient visit to perform the test.
*The results can be available within 24 hours.
*There are no boosted responses that are measured by subsequent tests.
*A history of previous BCG (bacillus Calmette-Guérin) vaccination does not yield a false-positive IGRA test result.
| style="padding: 5px 5px; background: #F5F5F5;" |
*The blood samples should be processed within 8-30 hours after collection while white blood cells are still viable.
*Errors in collecting or transporting blood specimens or in performing and interpreting the assay may reduce the accuracy of IGRAs.
*There is limited data on the use of IGRAs to predict who will progress to TB disease in the future.
*There is also limited data on the use of IGRAs for:


The gun injects [[Mantoux test|purified protein derivative]] equivalent to 100,000 units per mL to the skin over the flexor surface of the left forearm in a circular pattern of six. The test is read between 2 and 7 days later. The injection must not be into sites containing superficial veins.
:*Children younger than 5 years of age
:*Persons recently exposed to M. tuberculosis
:*Immunocompromised persons
:*Serial testing


The reading of the Heaf test is defined by a scale:
*It may be expensive
|-
| colspan="2" style="padding: 5px 5px; background: #F5F5F5;" |<SMALL>Table adapted from CDC Interferon-Gamma Release Assays<ref name="CDC TST">{{cite web|url= http://www.cdc.gov/tb/publications/factsheets/testing/IGRA.htm|title= CDC Interferon-Gamma Release Assays (IGRAs) - Blood Tests for TB Infection }}</ref></SMALL>
|}


*Negative - No induration, maybe 6 minute puncture scars
====CDC Recommendations on When to Use IGRA Tests  <small><small><SMALL> Adapted from CDC Interferon-Gamma Release Assays<ref name="CDC TST">{{cite web|url= http://www.cdc.gov/tb/publications/factsheets/testing/IGRA.htm|title= CDC Interferon-Gamma Release Assays (IGRAs) - Blood Tests for TB Infection }}</ref></SMALL></small></small>====
*Grade 1 - 4-6 papules (also considered negative)
*Grade 2 - Confluent papules form indurated ring (positive)
*Grade 3 - Central filling to form disc (positive)
*Grade 4 - Disc >10 mm with or without blistering (strongly positive)


Grades 1 and 2 may be the result of previous BCG or avian tuberculosis.  
*[[Interferon-γ release assays|IGRAs]] can also be used in stead of (but not in addition to) [[Mantoux test|TST]] in all conditions in which [[Centers for Disease Control and Prevention|CDC]] recommends TST as an aid in diagnosing [[Mycobacterium tuberculosis|M. tuberculosis]] infection, with preferences and particular considerations noted below.
*Contact [[investigations]], testing during [[pregnancy]], in addition to [[screening]] of [[health care workers]], and others undergoing serial evaluation for [[Mycobacterium tuberculosis|M. tuberculosis]] infection.
*In spite of the indication of a preference, the use of the alternative test ([[FDA]]-approved [[Interferon-γ release assays|IGRA]] or [[Mantoux test|TST]]) are approved medical and [[public health]] practice.
*We should be alert in interpretation when testing particular populations due to limited data on the use of [[Interferon-γ release assays|IGRAs]]


Children who have a grade 3 or 4 reaction require X-ray and follow-up.
*Populations in which [[Interferon-γ release assays|IGRAs]] are preferred for testing:


The equivalent [[Mantoux test]] positive levels done with 10 TU (0.1 mL 100 TU/mL, 1:1000) are:
:*Individuals who received [[BCG]] (either as a [[vaccine]] or for [[Cancer (medicine)|cancer]] therapy)
*0-4 mm induration (Heaf 0-1)
:*Individuals from groups that historically have less chances of coming back for [[Mantoux test|TST]] reading.
*5-14 mm induration (Heaf 2)
*&gt;15 mm induration (Heaf 3-4)


The [[Mantoux test]] is preferred in the United States for the diagnosis of tuberculosis; multiple puncture tests, such as the Heaf test and [[Tine test]], are not recommended.
*[[Mantoux test|TST]] is better than [[Interferon-γ release assays|IGRAs]] for children less than 5 years of age.
*As with [[Mantoux test|TST]], [[Interferon-γ release assays|IGRAs]] generally should not be used for testing individuals who have a low risk of [[infection]] and a low risk of  [[tuberculosis]] disease.
 
Routine testing with [[Mantoux test|TST]] and [[Interferon-γ release assays|IGRA]] is not recommended, but results from both tests may be useful in the following conditions:
 
{| style="border: 0px; font-size: 90%; margin: 3px; width: 700px" align="center"
! style="background: #4479BA; width: 300px;" |{{fontcolor|#FFF|When the initial test is '''negative''' and:}}
! style="background: #4479BA; width: 300px;" |{{fontcolor|#FFF|When the initial test is '''positive''' and:}}
|-
| style="padding: 5px 5px; background: #F5F5F5;" |
*The risk for infection, the risk for progression to active disease, and the risk for a bad outcome are high (e.g., HIV-infected individuals or children under 5 years of age who are exposed to an individual with infectious TB).
*Presence of clinical suspicion for TB disease (e.g., signs, symptoms, and/or radiographic evidence suggestive of TB disease) and confirmation of M. tuberculosis infection is needed.
*Getting a positive result from a second test as evidence of infection increases detection sensitivity of the test.
| style="padding: 5px 5px; background: #F5F5F5;" |
*Another evidence of infection is needed to encourage acceptance and adherence (e.g., foreign-born healthcare workers who believe their positive TST is due to BCG). A positive IGRA may necessitate greater acceptance of treatment for LTBI as compared with a positive TST alone.
*The individual has a low risk of both infection as well as progression from infection to TB disease. Requiring a positive result from the second test as evidence of infection increases the probability that the test reflects infection. An alternative is to suppose, without additional testing, that the initial result is a false positive or that the risk for the disease does not need additional evaluation or treatment, regardless of test results.
|-
| colspan="2" style="padding: 5px 5px; background: #F5F5F5;" |<SMALL>Table adapted from CDC<ref name="CDC TST">{{cite web|url= http://www.cdc.gov/tb/publications/factsheets/testing/IGRA.htm|title= CDC Interferon-Gamma Release Assays (IGRAs) - Blood Tests for TB Infection }}</ref></SMALL>
|}


===Drug Resistance===
*Moreover, repeating an [[Interferon-γ release assays|IGRA]] or doing a [[TST]] may be of value when the initial [[Interferon-γ release assays|IGRA]] result is indeterminate, borderline, or invalid and a reason for testing persists.
For all patients, the initial ''M. tuberculosis'' isolate should be tested for drug resistance. It is crucial to identify drug resistance as early as possible to ensure effective treatment. Drug susceptibility patterns should be repeated for patients who do not respond adequately to treatment or who have positive culture results despite 3 months of therapy. Susceptibility results from laboratories should be promptly reported to the primary health care provider and the state or local TB control program.
*Several negative results from any combination of these tests do not exclude [[Mycobacterium tuberculosis|M. tuberculosis]] infection. We should take some steps to minimize unnecessary and misleading testing of individuals at low risk.
*Choosing the best [[test]] or combination of tests for detection of [[Mycobacterium tuberculosis|M. tuberculosis]] [[infection]] should be made according to the causes and the context for testing, test availability, and overall cost of testing.


==References==
==References==
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[[Category:Disease]]
[[Category:Disease]]
[[Category:Infectious disease]]
[[Category: Pulmonology]]
[[Category:Pulmonology]]
[[Category:Needs overview]]
[[Category:Primary care]]
[[Category:Bacterial diseases]]
[[Category:Bacterial diseases]]
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2]; Alejandro Lemor, M.D. [3]

Overview

Routine laboratory exams are usually normal. The presence of acid-fast-bacilli (AFB) on a sputum smear or another specimen usually indicates TB disease and a positive culture for M. tuberculosis confirms the diagnosis. Other examples of laboratory tests are urinalysis, peritoneal fluid, or CSF analysis and Interferon-Gamma release assays (IGRA).

Laboratory Findings

Routine laboratory tests are usually normal. In some patients, the subsequent abnormalities could also be found:

Acid-Fast Bacilli

Acid-fast-bacilli in sputum smear

Presence of acid-fast-bacilli (AFB) on sputum smear or on another specimen usually indicates TB disease. Although acid-fast microscopy is easy and quick, it does not confirm a diagnosis of Tuberculosis as some acid-fast-bacilli are not M. tuberculosis. Consequently, a culture is done on all initial samples for confirmation of the diagnosis.

Sputum smears and cultures should be performed to detect acid-fast bacilli if the patient is producing sputum. The best method for this is fluorescence microscopy (auramine-rhodamine staining), which is more sensitive than conventional Ziehl-Neelsen staining.[1]

In case of inability of sufficient sputum production, specimens can be obtained by inducing sputum, gastric washings, a laryngeal swab, bronchoscopy with bronchoalveolar lavage, or fine-needle aspiration of a collection. A comparative study reported that inducing three sputum samples is more sensitive than three gastric washings.[2]

Other mycobacteria are also acid-fast. If the smear is positive, PCR or gene probe testing can differentiate M. tuberculosis from other mycobacteria. Even if sputum smear is negative, tuberculosis cannot be excluded without obtaining negative cultures.

Culture

A positive culture for M. tuberculosis confirms the diagnosis of TB disease. Culture examinations are crucial and should be done on all specimens, regardless of AFB smear results. Laboratories are necessary to report positive results on smears and cultures within 24 hours by telephone or fax to the primary health care provider and to the state or local TB control program, as needed by law.

Many types of cultures are available for M. tuberculosis, including Löwenstein-Jensen (LJ), Kirchner, or Middlebrook media. [3]. Culture of Mycobacteria often takes 4--8 weeks to grow and can help distinguish from several types of mycobacteria. Other kinds of culture are available, this include automated systems in which the mycobacteria grow at a faster rate. MB/BacT, BACTEC 9000, as well as the Mycobacterial Growth Indicator Tube (MGIT). The microscopic-observation drug-susceptibility (MODS) culture is considered a faster and more accurate method [4][5].

Culture: Distinctive clusters of colorless Mycobacterium tuberculosis
Löwenstein-Jensen media with Mycobacterium tuberculosis

A sample of pleural exudate should be analyzed by cytopathology or at a cell count lab. Samples are often lymphocyte predominant, and cytopathology is more accurate than cell count labs at detecting lymph. If there is more fluid present, then an AFB lab is more appropriate. Sometimes, a pleural exudate lab test find sterile pyuria (particularly in HIV positive patients), but overall this finding is fairly uncommon. Most extra-pulmonary TB is paucibacillary, hence the yield of tests is very low, and a negative test result does not exclude tuberculosis infection.

Drug Resistance

For all patients, the initial M. tuberculosis isolate should be tested for drug resistance. It is necessary to identify drug resistance as early as possible to ensure effective treatment. Drug susceptibility testing has to be repeated for patients who do not respond adequately to treatment or who have positive culture results despite 3 months of therapy. Susceptibility results from laboratories have to be reported to the primary health care provider and the state or local TB control programs.

Fluid Analysis

Urinalysis

Interferon-Gamma Release Assays (IGRAs)

Interferon-Gamma Release Assays (IGRAs) are whole-blood tests that aids in diagnosing Mycobacterium tuberculosis infection, but they do not differentiate latent tuberculosis infection (LTBI) from tuberculosis disease. Two IGRAs tests that are approved by the U.S. Food and Drug Administration (FDA) and commercially available in the U.S include the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) and the T-SPOT®.TB test (T-Spot).

IGRAs measure a person’s immune reactivity to M. tuberculosis antigen. White blood cells from most individuals that have been infected with M. tuberculosis will produce interferon-gamma (IFN-g) when mixed with antigens (substances that can produce an immune response) derived from M. tuberculosis.

To do this test, fresh blood samples should be mixed with antigens and controls. The antigens, testing methods, and interpretation criteria for IGRAs are different.

Differences in Currently Available IGRAs
QuantiFERON T-SPOT
Initial Process Process whole blood in 16 hours Process peripheral blood mononuclear cells (PBMCs) within 8 hours, or if T-Cell Xtend® is used, within 30 hours
M. tuberculosis Antigen Single mixture of synthetic peptides representing ESAT-6, CFP-10 & TB7.7. Separate mixtures of synthetic peptides representing ESAT-6 & CFP-10
Measurement Interferon-γ concentration Number of IFN-g producing cells (spots)
Possible Results Positive, negative, indeterminate Positive, negative, indeterminate, borderline
Table adapted from CDC [6]
Advantages and Disadvantages of IGRAs
Advantages Disadvantages
  • It requires a single patient visit to perform the test.
  • The results can be available within 24 hours.
  • There are no boosted responses that are measured by subsequent tests.
  • A history of previous BCG (bacillus Calmette-Guérin) vaccination does not yield a false-positive IGRA test result.
  • The blood samples should be processed within 8-30 hours after collection while white blood cells are still viable.
  • Errors in collecting or transporting blood specimens or in performing and interpreting the assay may reduce the accuracy of IGRAs.
  • There is limited data on the use of IGRAs to predict who will progress to TB disease in the future.
  • There is also limited data on the use of IGRAs for:
  • Children younger than 5 years of age
  • Persons recently exposed to M. tuberculosis
  • Immunocompromised persons
  • Serial testing
  • It may be expensive
Table adapted from CDC Interferon-Gamma Release Assays[6]

CDC Recommendations on When to Use IGRA Tests Adapted from CDC Interferon-Gamma Release Assays[6]

  • IGRAs can also be used in stead of (but not in addition to) TST in all conditions in which CDC recommends TST as an aid in diagnosing M. tuberculosis infection, with preferences and particular considerations noted below.
  • Contact investigations, testing during pregnancy, in addition to screening of health care workers, and others undergoing serial evaluation for M. tuberculosis infection.
  • In spite of the indication of a preference, the use of the alternative test (FDA-approved IGRA or TST) are approved medical and public health practice.
  • We should be alert in interpretation when testing particular populations due to limited data on the use of IGRAs
  • Populations in which IGRAs are preferred for testing:
  • Individuals who received BCG (either as a vaccine or for cancer therapy)
  • Individuals from groups that historically have less chances of coming back for TST reading.
  • TST is better than IGRAs for children less than 5 years of age.
  • As with TST, IGRAs generally should not be used for testing individuals who have a low risk of infection and a low risk of tuberculosis disease.

Routine testing with TST and IGRA is not recommended, but results from both tests may be useful in the following conditions:

When the initial test is negative and: When the initial test is positive and:
  • The risk for infection, the risk for progression to active disease, and the risk for a bad outcome are high (e.g., HIV-infected individuals or children under 5 years of age who are exposed to an individual with infectious TB).
  • Presence of clinical suspicion for TB disease (e.g., signs, symptoms, and/or radiographic evidence suggestive of TB disease) and confirmation of M. tuberculosis infection is needed.
  • Getting a positive result from a second test as evidence of infection increases detection sensitivity of the test.
  • Another evidence of infection is needed to encourage acceptance and adherence (e.g., foreign-born healthcare workers who believe their positive TST is due to BCG). A positive IGRA may necessitate greater acceptance of treatment for LTBI as compared with a positive TST alone.
  • The individual has a low risk of both infection as well as progression from infection to TB disease. Requiring a positive result from the second test as evidence of infection increases the probability that the test reflects infection. An alternative is to suppose, without additional testing, that the initial result is a false positive or that the risk for the disease does not need additional evaluation or treatment, regardless of test results.
Table adapted from CDC[6]
  • Moreover, repeating an IGRA or doing a TST may be of value when the initial IGRA result is indeterminate, borderline, or invalid and a reason for testing persists.
  • Several negative results from any combination of these tests do not exclude M. tuberculosis infection. We should take some steps to minimize unnecessary and misleading testing of individuals at low risk.
  • Choosing the best test or combination of tests for detection of M. tuberculosis infection should be made according to the causes and the context for testing, test availability, and overall cost of testing.

References

  1. ↑ Steingart K, Henry M, Ng V; et al. (2006). "Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review". Lancet Infect Dis. 6 (9): 570&ndash, 81. doi:10.1016/S1473-3099(06)70578-3.
  2. ↑ Brown M, Varia H, Bassett P, Davidson RN, Wall R, Pasvol G (2007). "Prospective study of sputum induction, gastric washing, and bronchoalveolar lavage for the diagnosis of pulmonary tuberculosis in patients who are unable to expectorate". Clin Infect Dis. 44 (11): 1415–20. doi:10.1086/516782. PMID 17479935.
  3. ↑ Drobniewski F, Caws M, Gibson A, Young D (2003). "Modern laboratory diagnosis of tuberculosis". Lancet Infect Dis. 3 (3): 141–7. PMID 12614730.
  4. ↑ Moore D, Evans C, Gilman R, Caviedes L, Coronel J, Vivar A, Sanchez E, Piñedo Y, Saravia J, Salazar C, Oberhelman R, Hollm-Delgado M, LaChira D, Escombe A, Friedland J (2006). "Microscopic-observation drug-susceptibility assay for the diagnosis of TB". N Engl J Med. 355 (15): 1539–50. PMID 17035648.
  5. ↑ Minion, Jessica; Leung, Erika; Menzies, Dick; Pai, Madhukar (2010). "Microscopic-observation drug susceptibility and thin layer agar assays for the detection of drug resistant tuberculosis: a systematic review and meta-analysis". The Lancet Infectious Diseases. 10 (10): 688–698. doi:10.1016/S1473-3099(10)70165-1. ISSN 1473-3099.
  6. ↑ 6.0 6.1 6.2 6.3 "CDC Interferon-Gamma Release Assays (IGRAs) - Blood Tests for TB Infection".

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