Received: 26 September 2019 

|
  Revised: 7 February 2020 
|
  Accepted: 9 February 2020

DOI: 10.1111/crj.13166

ORIGINAL ARTICLE

Tuberculin skin test and predictive host factors for

false-negative results in patients with pulmonary and
extrapulmonary tuberculosis

João Almeida Santos1,2,3   | Raquel Duarte4,5   | Carla Nunes1,3

1
Escola Nacional de Saúde Pública,
Universidade NOVA de Lisboa, Lisboa,
Abstract
Portugal Introduction: Tuberculin skin test (TST) has been the standard test for screening for
2
Instituto Nacional de Saúde Dr. Ricardo Mycobacterium tuberculosis infection for decades. Identifying persons with latent
Jorge, Lisboa, Portugal
tuberculosis infection (LTBI) is crucial, as they constitute a reservoir that sustains the
3
Centro de Investigação em Saúde Pública,
global tuberculosis (TB) epidemic. However, different factors, such as HIV infec-
Universidade NOVA de Lisboa, Lisboa,
Portugal tion, can lower the sensitivity of the test.
4
Centro Diagnóstico Pneumológico de Vila Objectives: The aim of this study was to determine the TST sensitivity in active
Nova de Gaia, Vila Nova de Gaia, Portugal TB patients and to ascertain risk factors that could be associated with false-negative
5
Faculdade de Medicina da Universidade do
results.
Porto, Porto, Portugal
Methods: Retrospective cohort study of all active TB notifications with a TST re-
Correspondence sult (n = 8833), from 2008 to 2015. TST results were interpreted using a 5 mm and
João Almeida Santos, Epidemiology and
10 mm cutoff. Bivariate and multivariate logistic regression analysis were used to
Statistics Department, Escola Nacional
de Saúde Pública, Universidade NOVA evaluate the association of sociodemographic and clinical factors with false-negative
de Lisboa, Avenida Padre Cruz 1600-560 TST results and to develop predictive risk models.
Lisboa, Portugal.
Email: jpa.santos@outlook.pt
Results: TST presented an overall sensitivity of 63.8% (5 mm) and 56.1% (10 mm).
HIV infection was the risk factor with the strongest association with false-negative
Funding information results (aOR 4.65-5  mm; aOR 5.05-10  mm). Other factors such as chronic renal
Fundação para a Ciência e a Tecnologia,
Grant/Award Number: PTDC/SAU- failure (CRF) (aOR 1.55-5 mm; aOR 1.73-10 mm), alcohol abuse (aOR 1.52-5 mm;
PUB/31346/2017 aOR 1.31-10 mm), drug abuse (aOR 1.90-5 mm; aOR 1.76-10 mm) or age ≥65 years
(OR 1.69-5 mm and 10 mm) were also associated with a probability of false-negative
results.
Conclusion: These results highlight the importance of knowing which factors influ-
ence TST results, such as HIV status, substance abuse or age, thus improving its
usefulness as a screening method for LTBI.

KEYWORDS
HIV infection, latent tuberculosis, preventive medicine, public health, tuberculin test, tuberculosis

1  |   IN T RO D U C T ION (TB) epidemic.1 People with LTBI have no signs or symp-

Diagnosis and treatment of latent tuberculosis infections
(LTBI) is an essential component of the End TB Strategy, a
global strategy endorsed by the World Health Organization
(WHO) to control and ultimately eliminate the tuberculosis
toms of TB disease and are not infectious, but are at risk of
developing active TB during their lifetime and become the
source of transmission for new cases of infection.2
Considering that approximately 1.7 billion people are esti-
mated to be latently infected with Mycobacterium tuberculosis,3

Clin Respir J. 2020;14:541–548. wileyonlinelibrary.com/journal/crj © 2020 John Wiley & Sons Ltd    541 |
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542       ALMEIDA SANTOS et al.
the implementation of strategies targeting LTBI diagnosis and
treatment becomes even more relevant to put a stop to the TB
epidemic. The potential benefit of treatment needs to be care-
fully balanced through the systematic screening of population
groups who are considered to be at greater risk of developing
TB,4 namely people living with human immunodeficiency virus
(HIV).
TB and HIV infection are inextricably intertwined. On the
one hand, TB is the leading cause of death among people
living with HIV, even within those taking antiretroviral ther-
apy.1 On the other hand, HIV is one of the highest risk factors
of progressing to active TB disease,1 with the increased risk
of developing TB being discernable as early as HIV sero-
conversion and further exacerbates as CD4 + T cell counts
decrease.5,6 WHO has established guidelines for targeted
LTBI testing and treatment, that recommends that high-risk
populations, such as people living with HIV or contacts of
pulmonary TB cases should be systematically screened for
M. tuberculosis infection.1,7
The tuberculin skin test (TST) is one of the oldest and
most widely used screening test in clinical practice and has
been the standard method for identifying individuals poten-
tially infected with M. tuberculosis. Important advantages of
the TST is its low cost, simplicity, no need for differentiated
infrastructures and robust interpretation based on extensive
published literature.8
However, different factors can lower the sensitivity of
this test and, consequently, its application in any group of
patients can yield a wide range of results, from the pres-
ence of a reaction in uninfected people to the complete ab-
sence of a reaction in cases with confirmed TB disease.9
Immunosuppressive conditions (eg, HIV infection, cancer),
immunosuppressive drugs, age and overwhelming acute
illness (eg, end-stage renal disease), can affected the ca-
pability of the immune system to respond to the test, pro-
moting the occurrence of false-negative TST results.10,11
Unfortunately, the factors that may promote false-negative
results are also associated with an increased risk of progres-
sion from latent infection to active disease.2,12 Therefore,
the identification of factors associated with false-negative
results will help improve TST usefulness as a diagnostic
aid for LTBI.
There is no available gold standard for LTBI diagnosis
against which the TST can be evaluated.13 However, using in-
direct evidence such as TST results from patients with a defini-
tive TB diagnosis it is possible to establish the sensitivity of the
test and through knowledge of epidemiological data, determine
factors that may be associated with false-negative results.
Thus, the aim of the study was to determine the sensi-
tivity of the TST in active TB patients and to ascertain risk
factors that could be associated with false-negative TST
results.
2  |  M ATERIAL S AND M ETHOD S
2.1  |  Study design and data source
Retrospective cohort study using data from TB cases noti-
fied in the Portuguese National Tuberculosis Surveillance
System (SVIG-TB), from 2008 to 2015. SVIG-TB data-
base is generated by direct compulsory reporting by health
care providers and the data from this official system of no-
tification is complemented and updated during TB cases
follow-up. Patients notified in the database are diagnosed
based on laboratory confirmed TB and/or based on clinical,
biological and radiological findings, and a favorable TB
treatment response.
2.2  |  Study data
The study included all patients notified in the SVIG-TB da-
tabase with active TB (pulmonary and extrapulmonary TB)
and a TST result.
The sociodemographic and clinical variables analyzed
were sex, age group (≤15, 16-64, ≥65  years), comorbidi-
ties (chronic renal failure (CRF) in dialysis, oncologic dis-
eases, inflammatory diseases, HIV infection and diabetes),
substance abuse (alcohol and drug abuse) and site of disease
(pulmonary or extrapulmonary TB). TST results were the
dependent variable (event: false-negative results).
2.3  |  Statistical analysis
TST induration measurements were interpreted using ≥5 mm
(TST-5 mm) and ≥10 mm (TST-10 mm) as cutoff points,14
and converted into positive or negative results.
TST sensitivity15 was calculated with 95% confidence in-
tervals for all patients and stratified according to sociodemo-
graphic and clinical variables.
The effect of each variable on the occurrence of
false-negative TST results was evaluated using bivariate
logistic regressions, based on crude and adjusted odds ratio
(OR-crude; aOR-adjusted for age and sex) and 95% confi-
dence intervals (95%CI). The significance level was set at
0.05.
Final multivariate logistic models were developed, with
forward stepwise (Likelihood Ratio) method, logit func-
tion (entry-0.05; removal-0.10) and included variables
that were significant in bivariate analyses and associated
with false-negative results. Based on guidelines to deter-
mine a positive TST reaction, the HIV infection variable
was only considered in the final predictive model using a
5  mm cutoff.14 Receiver Operating Characteristic (ROC)
ALMEIDA SANTOS et al.
curve was used as a measure of the model's predictive
discrimination.15
Statistical analyses were performed using IBM SPSS
Statistics for Windows, version 23 (IBM Corp.) and Stata
Statistical Software, Release 14 (StataCorp, College
Station).
3  |   R E S U LTS
Of the 20 638 patients notified with active TB (2008-2015)
in the SVIG-TB database, 8833 (42.8%) had a TST result.
The mean (±standard deviation) age of these patients was
44.0  years (±19.0), ranging from less than 1 to 99  years.
Portugal was the main country of origin (n = 7562; 85.6%),
followed by African countries (n = 867; 9.8%). HIV infection
was the most common comorbidity and CRF was the least
frequent.
3.1  |  TST sensitivity
TST overall sensitivity was 63.8%, when using a 5 mm cut-
off (TST-5  mm) and 56.1%, when using a 10  mm cutoff
(TST-10 mm), with a greater difference between cutoffs in
patients with CRF in dialysis and lower difference in younger
patients (≤15  years). For both cutoffs, the TST sensitivity
was higher in younger patients, inflammatory diseases and in
female patients. In contrast, the TST sensitivity was lower in
cases with HIV infection, CRF, drug abuse and older patients
(≥65 years). Table 1 shows the sensitivity results for total of
patients and stratified according to the sociodemographic and
clinical variables.
3.2  |  Risk factors for false-negative TST
From the 8833 patients included in the study, 3197 (36.2%)
presented a negative TST-5 mm and 3878 (43.9%) a negative
TST-10 mm. Tables 2 and 3 present the results of bivariate
analysis and multiple logistic regressions.
For both cutoffs, crude analysis indicates that patients
with HIV infection, CRF, drug abuse, age ≥65 years, al-
cohol abuse and diabetes had a statistically significant
association with a higher probability of false-negative re-
sults. HIV infection presented the higher association (OR
4.31, P < 0.001-5 mm; OR 4.72, P < 0.001-10 mm) and
diabetes the lower association with false-negative results
(OR 1.28, P = 0.014-5 mm; OR 1.33, P = 0.002). On the
contrary, patients with age ≤15  years had a statistically
significant association with a low probability of false-neg-
ative results.
  
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Site of disease, oncologic and inflammatory diseases
were not statistically associated with false-negative results.
When adjusting by sex and age (TST-5  mm), patients
with CRF (OR 1.87; P = 0.007 vs aOR 1.55, P = 0.061)
and diabetes (OR 1.28; P = 0.014 vs aOR 1.07, P = 0.484)
were no longer statistically associated with false-negative
results. For TST-10  mm, only patients with diabetes pre-
sented similar results (OR 1.37; P  =  0.002 vs aOR 1.15,
P = 0.168).
The final multivariate logistic model for TST-5  mm in-
cluded the following variables: sex, age, HIV infection and
alcohol abuse. As for the TST-10  mm, the model included
the variables: sex, age, alcohol abuse, drug abuse, diabetes
and CRF. Although presenting a statistically significant as-
sociation with false-negative results, HIV infection was not
incorporated in the TST-10  mm final model, as previously
stated in the methods section.
Area under the ROC curve of these final models was
62.5% (95%CI 61.2-63.9) for TST-5 mm and 59.2% (95%CI
58.0-60.5) for TST-10 mm.
The nomogram (Figures 1 and 2) represent graphically
the final predictive models for false-negative TST-5  mm
and TST-10 mm, in order to facilitate the use of the infor-
mation obtained in the model for possible clinical decision
making.
4  |  DISCUSSION
In our study, the HIV infection presented the higher association
with false-negative TST results. Patients co-infected with HIV
presented the lowest TST sensitivity (32.9%-5  mm; 24.2%-
10 mm) with results 30% lower than the overall sensitivity and
a rate of false-negative results of 67.1% (TST-5 mm) and 75.8%
(TST-10 mm). These patients were statistically associated with
a higher probability of presenting a false-negative TST result
with either cutoff, even after adjusted to sex and age, associa-
tion that mirrors the sensitivity obtained in the study. After ad-
justing for age and sex, HIV-infected patients were close to five
times more likely to have false-negative TST results than were
patients without HIV infection. Mazurek et al also documented
that HIV infection was strongly associated with false-negative
TST results and that, after adjusting for age, HIV-infected pa-
tients were 13.5 times more likely to have false-negative TST
results than HIV-uninfected patients.16
This reduced sensitivity is a consequence of an im-
paired cell mediated immunity, common in immunocom-
promised cases such as HIV-infected patients, that limits the
delayed-type hypersensitivity response on which the TST
is based.17 Similar reduced sensitivities were established
in studies of Yu et al (12.9%), Jiang et al (25%), Kabeer
et al (31%) and Stavri et al (39%), where patients with TB
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544       ALMEIDA SANTOS et al.

T A B L E 1   TST sensitivity (N = 8833) using 5 mm (TST-5 mm) and 10 mm (TST-10 mm) cutoffs according to sex, age group, comorbidities
(chronic renal failure, oncologic disease, inflammatory disease, HIV infection and diabetes), substance abuse (alcohol or drug abuse) and site of
disease (pulmonary or extrapulmonary TB)

TST-5 mm TST-10 mm

Sensitivity % Sensitivity %
Variables n/N (%) Positive (n) (95%CI) Positive (n) (95%CI)
Total (N = 8833) 5636 63.8 (62.8-64.8) 4955 56.1 (55.1-57.1)
Sex Female 5443/8833 (61.6) 2266 66.8 (65.2-68.4) 2046 60.4 (58.7-62.0)
Male 3390/8833 (38.4) 3370 61.9 (60.6-63.2) 2909 53.4 (52.1-54.8)
Age group ≤15 years 413/8829 (4.7) 329 79.7 (75.8-83.5) 306 74.1 (69.9-78.3)
16-64 years 6991/8829 (79.1) 4556 65.2 (64.1-66.3) 4014 57.4 (56.3-58.6)
≥65 years 1425/8829 (16.1) 749 52.6 (49.9-55.2) 633 44.4 (41.8-47.0)
Comorbidities Chronic renal 76/8833 (0.9) 39 51.3 (40.1-62.6) 29 38.2 (27.2-49.1)
failure
Oncologic diseases 246/8833 (2.8) 149 60.6 (54.4-66.7) 125 50.8 (44.6-57.1)
Inflammatory 154/8833 (1.7) 103 66.9 (59.5-74.3) 90 58.4 (50.7-66.2)
diseases
HIV infection 756/7841 (8.6) 249 32.9 (29.7-36.4) 183 24.2 (21.3-27.4)
Diabetes 439/8833 (5.0) 256 58.3 (53.7-62.9) 214 48.7 (44.1-53.4)
Substance abuse Alcohol abuse 903/8471 (10.2) 500 55.4 (52.1-58.6) 448 49.6 (46.4-52.9)
Drug abuse 747/8529 (8.5) 384 51.4 (47.8-54.9) 331 44.3 (40.7-47.9)
Site of disease Pulmonary 6188/8833 (70.1) 3927 63.5 (62.3-64.7) 3473 56.1 (54.9-57.4)
Extrapulmonary 2645/8833 (29.9) 1709 64.6 (62.8-66.4) 1482 56.0 (54.1-57.9)

T A B L E 2   Association between false-negative TST-5 mm results and sociodemographic and clinical variables among patients with notified TB

Bivariate analysis Multivariate logistic

Bivariate analysis (crude) (adjusted for age and sex) regression analysis (FR)

Variables OR (95%CI) P OR (95%CI) P OR (95%CI) P

b
Sex Male/Female   1.24 (1.13-1.36) <0.001     1.14 (1.03-1.27) 0.12
a
Age groups   ≤15 years 0.45 (0.37-0.61) <0.001     0.63 (0.46-0.85) 0.003
≥65 years 1.69 (1.51-1.90) <0.001     1.98 (1.74-2.26) <0.001
Comorbidities Chronic renal 1.87 (1.19-2.94) 0.007 1.55 (0.98-2.46) 0.061  
(Yes/Nob ) failure
Oncologic 1.15 (0.89-1.49) 0.284 0.91 (0.70-1.19) 0.494  
diseases
Inflammatory 0.87 (0.62-1.22) 0.423 0.75 (0.53-1.06) 0.101  
diseases
HIV infection 4.31 (3.67-5.05) <0.001 4.65 (3.96-5.47) <0.001 4.31 (3.64-5.11) <0.001
Diabetes 1.28 (1.05-1.55) 0.014 1.07 (0.88-1.31) 0.484  
Substance abuse Alcohol abuse 1.55 (1.35-1.79) <0.001 1.52 (1.32-1.76) <0.001 1.41 (1.20-1.65) <0.001
(Yes/Nob ) Drug abuse 1.82 (1.57-2.12) <0.001 1.90 (1.63-2.22) <0.001  
Site of disease ETB/PTBb  0.95 (0.87-1.05) 0.303 0.93 (0.84-1.02) 0.130    
Abbreviations: CI, confidence interval; ETB, extrapulmonary TB; FR, forward stepwise (LR); OR, odds ratio; PTB, pulmonary TB.
a
Reference category was 16-64 years.
b
Reference category.

and HIV coinfection presented a significant loss of TST sen- the leading cause of death among people living with HIV,1
sitivity and frequent cases of anergy.18-21 becomes clear that knowledge of HIV status is essential to
Given that HIV-infected patients have a much higher better interpret TST results. Not knowing this critical data
probability of progressing to active TB disease, and TB is of the person's clinical history may lead to underdiagnosis
ALMEIDA SANTOS et al.   
   545
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T A B L E 3   Association between false-negative TST-10 mm results and sociodemographic and clinical variables among patients with notified TB

Bivariate analysis Multivariate logistic

Bivariate analysis (crude) (adjusted for age and sex) regression analysis (FR)

Variables OR (95%CI) P OR (95%CI) P OR (95%CI) P

b
Sex Male/Female   1.33 (1.22-1.45) <0.001   1.22 (1.11-1.34) <0.001
a
Age groups   ≤15 years 0.47 (0.38-0.59) <0.001   0.51 (0.40-0.64) <0.001
≥65 years 1.69 (1.50-1.89) <0.001   1.79 (1.59-2.01) <0.001
Comorbidities Chronic renal failure 2.08 (1.31-3.32) 0.002 1.73 (1.08-2.77) 0.023 1.81 (1.13-2.91) 0.014
(Yes/Nob ) Oncologic diseases 1.24 (0.97-1.60) 0.091 0.99 (0.76-1.28) 0.916
Inflammatory diseases 0.91 (0.66-1.25) 0.554 0.78 (0.56-1.08) 0.136
HIV infection 4.72 (3.97-5.61) <0.001 5.05 (4.24-6.01) <0.001
Diabetes 1.37 (1.13-1.65) 0.002 1.15 (0.94-1.40) 0.168 1.22 (1.00-1.50) 0.048
Substance abuse Alcohol abuse 1.39 (1.21-1.60) <0.001 1.31 (1.14-1.51) <0.001 1.22 (1.05-1.42) 0.008
(Yes/Nob ) Drug abuse 1.73 (1.49-2.01) <0.001 1.76 (1.51-2.05) <0.001 1.68 (1.42-1.98) <0.001
Site of disease ETB/PTBb  1.00 (0.92-1.10) 0.935 0.99 (0.90-1.09) 0.889
Abbreviations: CI, confidence interval; ETB, extrapulmonary TB; FR, forward stepwise (LR); OR, odds ratio; PTB, pulmonary TB.
a
Reference category was 16-64 years.
b
Reference category.

F I G U R E 1   Nomogram for identification of patients at risk of false-negative TST (5 mm cutoff). How to read: locate patient status on each
of the horizontal lines (eg, HIV infection) representing individual information. Draw a straight line down to the 'Score' axis to determine what score
the patient will have for each factor. Sum up the scores for each factor and locate this sum on the 'Total score' axis and then draw a line straight up
from the 'Total score' axis until it intersects the horizontal line 'Probability (Prob)', this value corresponds to the expected probability of a false-
negative result

of latent infections, resulting in the maintenance of M. tu- likelihood of progression to active disease. Presently, treat-
berculosis reservoirs in the community and preventing the ment options for LTBI can reduce the risk of developing ac-
implementation of a treatment regimen that would reduce the tive TB by 60%-90%.1
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546       ALMEIDA SANTOS et al.
F I G U R E 2   Nomogram for identification of patients at risk of false-negative TST (10 mm cutoff). Indications of how to read the nomogram
are shown in Figure 1
Thus, to help prevent HIV-associated TB, the screening
for a potential M. tuberculosis infection should be associ-
ated with screening for HIV infection, as recommended in
the guidelines of WHO's End TB Strategy. Particularly in
vulnerable populations at increased risk of coinfection,
in order to achieve a more realistic interpretation of the
TST results and possibly identified potential false-negative
results.
Also, in view of our sensitivity results from HIV-TB
co-infected patients, the use of TST alone to detect cases
of M. tuberculosis infection in populations with a high in-
cidence of HIV might not be sufficient to achieve the goals
of ending the TB epidemic by 2035, as proposed by the
WHO. Using a multivariable approach integrating TST,
IGRA and other available diagnostic aids may provide a
more accurate strategy to maximize LTBI diagnosis and
treatment, in order to prevent reactivation TB in this vul-
nerable population.13
CRF, old age and alcohol and drug abuse are other risk
factors that we found that can lead to false-negative TST
results.
CRF was other comorbidity that was associated with
a lower TST sensitivity and statistically associated with a
higher probability of false-negative TST results with either
cutoff, although when adjusted to sex and age the association
was only statistically significant for TST-10 mm.
Patients with CRF have a 3-fold to 25-fold risk of de-
veloping TB, when compared to the general population,22
which makes CRF a significant risk factor for active TB.
However, kidney failure induces an immunosuppression
state23 that can result in significantly higher cases of
TST anergy in TB patients with CRF, than in the general
population.24
Our sensitivity results are in agreement with the liter-
ature, with the observation of anergy in more than 60% of
the cases. The sensitivity obtained in our study (32.8%) was
lower than that observed in other two studies that also deter-
mined the TST sensitivity in TB patients with CRF, 44.4%25
and 61.5%,26 using the 10 mm cutoff. However, in all three
studies the TST sensitivity was lower than desirable, espe-
cially in a population associated with an increased risk of
TB. Thus, because of its low sensitivity and association with
false-negative results, a negative TST result in patients with
CRF should be carefully evaluated.
Patients with age ≥65  years also presented a low TST
sensitivity. The decrease in TST sensitivity in older adults
may be because of decreasing immunity, as these patients
present a 5% decline in test positivity per decade after age
65  years.27 Acute or chronic diseases, malnutrition and the
biological changes associated with aging contribute to the
expected age-related diminution in immune responses and
consequently lead to a reduction in the TST sensitivity.28
However, studies that estimated TST sensitivity in TB
patients with more than 60  years presented higher values
than the ones obtained in our study (52.6%-5  mm; 44.4%
−10  mm), Choi et al obtained a TST sensitivity of 80.9%
(5 mm) and 77.3% (10 mm)29 and Cho et al a sensitivity of
59.1% (10 mm).30 The number of older patients involved in
ALMEIDA SANTOS et al.
the studies may explain these differences (68 and 19 patients
vs 1425 patients in our study), or that our study involved older
patients (351 patients had more than 80 years) witch can pro-
mote the occurrence of a higher number of anergy cases.31
In our study, we observed that as the age year progressed
the occurrence of false-negative results began to equal or even
surpass the positive results, with a growing frequency. This
change in the pattern of results begins at age 69 years, when
using the 5 mm cutoff, or from the age of 65, when using the
10  mm cutoff. These results corroborate that old age influ-
ences the ability to respond to TST,27 in which the older the
patient is the greater the likelihood of a false-negative result.
Therefore, our results show that age-associated changes in
the immune system must be taken into account in the evalu-
ation of the results from the tuberculin test, under penalty of
not being detected cases of infection in a highly susceptible
population.
Drug abuse and alcohol use disorders have been associ-
ated with a higher prevalence of LTBI and incidence of active
TB.32,33 Even though the data on drug and alcohol abuse was
ascertained by self-report and the degree of dependence is
unknown, patients who were identified as having a problem
with drug or alcohol presented a statistically significant asso-
ciation with a higher probability of false-negative TST results
with either cutoff, even when the analysis was adjusted for
age and sex. As TB disproportionally affects certain groups in
the population such as immigrants, homeless people or those
with a history of drug and alcohol abuse,34,35 these results
alert for the necessity of more studies, with more detailed
information on alcohol consumption and drug use in order to
better understand its potential association with false-negative
TST results.
Considering the final models, the area under the ROC
curve for TST-5 mm and TST-10 mm presented low capac-
ity to discriminate false-negative results, as in both cases the
area under the ROC curve was between 50% and 70%.36
Our study had some limitations. First, the presence of vari-
ables based on patient self-report (eg, alcohol abuse, drugs
abuse) may have led to a less accurate estimate of the impact
of these variables. Second, there is no information as to the
severity of the disease, which could influence the capability
to mount an immune response to the tuberculin. Third, using
active TB patients as a proxy for evaluating the sensitivity of
the TST has the disadvantage that patients with active TB can
present immunosuppression because of the disease itself, ham-
pering the ability to respond to the tuberculin. On the contrary,
this study involved a large number of patients with different
risk factors, which allowed observing the behavior of TST in
different settings, contributing to a better understanding of
how to use this test in populations with certain risk factors.
In conclusion, our study identified several risk factors
for TST false-negative results, such as HIV infection, CRF
on dialysis, age greater than 65 years, diabetes, alcohol and
  
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   547
drug abuse. These results indicate that in certain groups of
the population the negative results from the tuberculin test
should be interpreted with caution.
Of the factors assessed in the study, patients with TB
and HIV coinfection presented by far the lowest sensitivity
and the strongest statistically significant association with
false-negative results. These results suggest that the use
of the TST as a diagnostic method for screening LTBI in
persons co-infected with HIV may lead to underdiagnosis
and consequently undermine the success of the TB control
programs.
CONFLICT OF INTEREST
The authors report no conflicts of interest.
AUTHOR CONTRIBUTIONS
All authors made substantial contributions to the conception
and design of the study and all gave the final approval of the
version to be submitted.
Study design: Almeida Santos, Duarte, Nunes
Data analysis: Almeida Santos
Performed experiments: Almeida Santos, Nunes
ETHICS
Ethics committee approval and informed consent were not
required, as all patient data were obtained from the SVIG-TB
database that is fully anonymized.
ORCID
João Almeida Santos  https://orcid.
org/0000-0002-8564-1098
Raquel Duarte  https://orcid.org/0000-0003-2257-3099
Carla Nunes  https://orcid.org/0000-0003-4562-1057
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How to cite this article: Almeida Santos J, Duarte R,
Nunes C. Tuberculin skin test and predictive host
factors for false-negative results in patients with
pulmonary and extrapulmonary tuberculosis. Clin
Respir J. 2020;14:541–548. https://doi.org/10.1111/
crj.13166