INT J TUBERC LUNG DIS 14(6):741–744
© 2010 The Union
Extra-pulmonary and smear-negative forms of tuberculosis
are associated with treatment delay and hospitalisation
J. Whitehorn,* H. Ayles,*† P. Godfrey-Faussett*
* London School of Hygiene & Tropical Medicine, London, UK; † ZAMBART (Zambia AIDS Related TB) Project,
Lusaka, Zambia
SUMMARY
SETTING:
Adult patients with tuberculosis (TB) recruited at the chest clinic of the University Teaching Hospital in Lusaka, Zambia, from 2003 to 2004.
O B J E C T I V E : To identify factors associated with delayed
treatment or hospitalisation.
D E S I G N : A cross-sectional survey of newly identified
adult patients with TB.
R E S U LT S : A total of 223 patients were included in the
analysis. Patients with smear-negative disease were
2.6 times more likely to be hospitalised than those with
smear-positive disease (95%CI 1.28–5.30), while patients
with extra-pulmonary disease were 3.42 times more
likely to be hospitalised than those with pulmonary disease (95%CI 1.75–6.66). Patients with smear-negative
disease were 2.81 times more likely to have experienced
overall delay than those with smear-positive disease
(95%CI 1.20–6.66).
D I S C U S S I O N : This analysis has demonstrated that patients with extra-pulmonary or smear-negative disease
are significantly more likely to be hospitalised. Patients
with smear-negative disease are also more likely to have
experienced treatment delay. These data reinforce the
urgent need for more robust diagnostic tests, particularly for smear-negative and extra-pulmonary disease.
As these forms of disease are more likely to be associated with the human immunodeficiency virus (HIV), the
data support earlier diagnosis and treatment of HIV
infection.
K E Y W O R D S : tuberculosis; Zambia; delay; diagnosis;
HIV
TUBERCULOSIS (TB) remains a major cause of disease and death globally.1 The burden of TB falls predominantly on countries of sub-Saharan Africa, where
it is closely associated with the human immunodeficiency virus (HIV) pandemic.1 In Zambia, where
the prevalence of HIV is 20%, TB is causing a public health crisis.2
Diagnosing TB remains a challenge.1 In Zambia,
diagnosis is largely dependent on sputum smear microscopy, which has low sensitivity for the diagnosis
of TB, particularly in the context of HIV co-infection
where smear-negative and extra-pulmonary forms of
disease are more common.3,4 The lack of effective diagnostic tools delays the diagnosis of TB in people
who have accessed health care.5,6 Furthermore, people
with symptoms suggestive of TB may delay seeking
health care.7
Diagnostic delay, whether patient-related or health
provider-related, leads to poor outcomes for individual patients and to increased spread of TB within the
community.5,8,9 Furthermore, outcomes for individual
patients admitted to hospital in sub-Saharan Africa
with TB are poor.9 More efficient pathways to diagno-
sis and treatment have the potential to improve individual patient outcomes and TB control efforts.10,11
AIMS AND METHODS
As delayed diagnosis and hospitalisation are associated with a worse prognosis, this study aimed to identify associated factors. We analysed part of the data
set that had been collected between 2003 and 2004
as part of a United Nations Development Programme/
World Bank/World Health Organization funded study
entitled ‘Timing and its significance in the diagnosis
of TB: a multinational, multicentre study’. The parent
study has not been published. The Zambian data had
not been previously analysed. This analysis was restricted to adult patients recruited at the chest clinic
of the University Teaching Hospital (UTH) in Lusaka,
the Zambian capital. The UTH in Lusaka is the only
teaching hospital in Zambia. It is a secondary referral
centre for Lusaka and a tertiary referral centre for the
rest of Zambia.
The original study involved a cross-sectional survey of newly diagnosed TB patients at UTH and a
Correspondence to: James Whitehorn, Clinical Research Unit, London School of Hygiene & Tropical Medicine, Keppel
Street, London WC1E 7HT, UK. Tel & Fax: (+44) 207 636 8636. e-mail: [email protected]
Article submitted 7 October 2009. Final version accepted 18 December 2009.
742
The International Journal of Tuberculosis and Lung Disease
prospective cohort study of these patients. The inclusion criteria for entry into the study were TB diagnosed
and started on treatment within the previous 2 months
and written informed consent. Smear-positive TB was
diagnosed by finding acid-fast bacilli (AFB) in a ZiehlNeelsen-stained sputum sample. Smear-negative TB
was diagnosed clinically and radiologically. TB culture facilities were not available. Extra-pulmonary
TB was diagnosed in some patients by finding AFB in
clinical samples, for example lymph node aspirates.
Some subjects from this patient group were started
on TB treatment on clinical suspicion, without a clear
diagnosis. It is likely that some of the patients in the
smear-negative and extra-pulmonary groups did not
have TB. Patients with chronic lung disease or previous TB were excluded.
The original study received ethical approval from
the University of Zambia Research Ethics Committee.
The present analysis received separate approval from
the London School of Hygiene & Tropical Medicine
Ethics Committee.
Data from the original study were entered into
an EpiData database (EpiData Association, Odense,
Denmark). For this analysis, data were transferred
to STATA v.9 (StataCorp, College Station, TX, USA).
The time from symptom onset to seeking health care
(patient time) and from seeking health care to starting
TB treatment (provider time) were calculated using
STATA. Overall time was the sum of patient and provider times. Categorical variables were created within
STATA for patient delay (patient time >3 weeks),
provider delay (provider time >2 weeks) and overall
delay (overall time >5 weeks).
The differences in categorical variables were calculated using χ2 tests. The odds of hospitalisation and
Table 1
delay for the different categorical variables were calculated. From this, odds ratios between categorical
variables were calculated. P < 0.05 was considered
statistically significant.
RESULTS
A total of 223 patients were included in the analysis:
119 were men (53%), 169 had pulmonary disease
(73%), 120 were smear-positive (54%), and 18 were
known to be HIV-positive (8%), while the HIV status
was not known for 195 patients (87%).
Patients with smear-negative disease were 2.6 times
more likely to be hospitalised than those with smearpositive disease (95%CI 1.28–5.30), while patients
with extra-pulmonary disease were 3.42 times more
likely to be hospitalised than those with pulmonary
disease (95%CI 1.75–6.66). The relationship between
hospitalisation, disease type and HIV status is illustrated in Table 1. Patients with smear-negative disease were 2.81 times more likely to have experienced
overall delay than those with smear-positive disease
(95%CI 1.20–6.66). The relationship between overall delay, disease type and HIV infection is illustrated
in Table 2.
DISCUSSION
Patients with extra-pulmonary TB were more than
three times more likely to be admitted to hospital than
those with pulmonary disease, while patients with
smear-negative TB were more than twice as likely to
be admitted as those with smear-positive disease. This
is likely to reflect the relative ease in diagnosing smearpositive TB. It is possible that some of these patients
Relationship between hospitalisation, delay, disease type and HIV status
Variable
Patient delay
Yes
No
Health provider delay
Yes
No
Overall delay
Yes
No
Disease type
Pulmonary
Extra-pulmonary
Smear status
Smear-positive
Smear-negative
Unknown
HIV status
Positive
Negative
Not known
Hospitalised
n (%)
Not hospitalised
n (%)
38 (50.7)
51 (54.8)
37 (49.3)
42 (45.2)
41 (57.7)
51 (48.1)
30 (42.3)
55 (51.9)
38 (55.9)
48 (50)
30 (44.1)
48 (50)
68 (42)
42 (71.2)
94 (58)
17 (28.8)
43 (36.1)
28 (59.6)
32 (72.7)
76 (63.9)
19 (40.4)
12 (27.3)
12 (66.7)
4 (40)
94 (48.7)
6 (33.3)
6 (60)
99 (51.3)
P value
Odds of
hospitalisation (95%CI)
OR (95%CI)
0.590
1.03 (0.653–1.62)
1.21 (0.807–1.83)
1
1.18 (0.641–2.18)
1.37 (0.853–2.19)
0.927 (0.807–1.83)
1.47 (0.801–2.71)
1
1.27 (0.785–2.04)
1.00 (0.670–1.49)
1.27 (0.677–2.37)
1
0.723 (0.530–0.988)
2.47 (1.41–4.34)
1
3.42 (1.75–6.66)
0.566 (0.389–0.822)
1.47 (0.823–2.64)
2.67 (1.37–5.18)
1
2.60 (1.28–5.30)
4.71 (2.10–10.6)
2.00 (0.751–5.33)
0.667 (0.188–2.36)
0.949 (0.716–1.26)
2.11 (0.754–5.88)
0.702 (0.191–2.58)
1
0.209
0.457
<0.001
<0.001
0.283
HIV = human immunodeficiency virus; CI = confidence interval; OR = odds ratio.
Treatment delay in TB
Table 2
743
Relationship between overall delay, disease type and HIV status
Variable
Disease type
Pulmonary
Extra-pulmonary
Smear status
Smear-positive
Smear-negative
Unknown
HIV status
Positive
Negative
Not known
Overall delay
n (%)
No overall delay
n (%)
54 (43.5)
14 (33.3)
70 (56.5)
28 (66.7)
35 (37.2)
20 (62.5)
10 (31.3)
59 (62.8)
12 (37.5)
22 (68.7)
3 (18.8)
1 (16.7)
64 (44.4)
13 (81.2)
5 (83.3)
80 (55.6)
P value
Odds of
overall delay (95% CI)
OR (95%CI)
0.771 (0.541–1.10)
0.500 (0.263–0.950)
1.54 (0.737–3.23)
1
0.593 (0.390–0.901)
1.67 (0.815–3.41)
0.455 (0.215–0.960)
1
2.81 (1.20–6.60)
0.766 (0.324–1.81)
0.231 (0.066–0.810)
0.200 (0.023–1.71)
0.800 (0.576–1.11)
0.288 (0.077–1.08)
0.250 (0.028–2.24)
1
0.245
0.019
0.066
HIV = human immunodeficiency virus; CI = confidence interval; OR = odds ratio.
did not actually have TB and that the higher admissions in these groups reflected diagnostic uncertainty
and perhaps a poor response to inappropriate treatment. The HIV status was not known for the majority of study participants. This may reflect the unavailability of antiretroviral treatment in Zambia at the
time of the study, resulting in lower uptake of HIV
testing. Extra-pulmonary and smear-negative TB are
more likely to be associated with HIV.3,4 It is possible
that these patients had other comorbidities associated
with immunosuppression, which may have meant they
were more likely to have needed admission. Furthermore, the diagnosis of extra-pulmonary and smearnegative TB is often difficult, and diagnosing these
types of TB may necessitate admission to hospital for
a diagnostic procedure.1,12
There was a statistically significant association
between smear status and overall delay. Patients
with smear-negative disease were more than twice as
likely to have experienced overall delay as those with
smear-positive disease. This is expected, as smearpositive TB is easier to diagnose provided sputum is
obtained. Smear-negative TB can be difficult to diagnose and often requires assessing the response to
antibiotic treatment as well as reviewing radiological
investigations.12
This study has demonstrated that extra-pulmonary
TB and smear-negative TB were associated with higher
rates of hospitalisation than for patients with pulmonary and smear-positive disease. Smear-negative and
extra-pulmonary TB are more likely to be associated
with HIV, although in this study the HIV status was
not known for the majority of participants. This association with immunosuppression may be reflected in
higher amounts of comorbidity and thus higher hospitalisation rates. The fact that smear-negative disease
was associated with more overall delay than smearpositive disease is consistent with results from other
studies.13–15 As these patients are more likely to be
co-infected with HIV and therefore potentially more
unwell, this delay may adversely affect outcome. Increasing age was associated with increased amounts
of overall delay, correlating with the findings of previous studies.7
More robust diagnostic and culture techniques are
urgently needed, particularly for extra-pulmonary and
smear-negative disease. The low sensitivity of smear
microscopy for pulmonary TB remains a significant
hurdle to effective TB control.6,12,13 Improved diagnostics are necessary both for patients with TB and to
protect those without TB from inappropriate, potentially toxic, treatment. As smear-negative and extrapulmonary forms of TB are associated with HIV,
earlier diagnosis and treatment of HIV infection is
likely to have a significant role to play in combating
these forms of TB.4,16
References
1 Frieden T R, Sterling T R, Munsiff S S, Watt C J, Dye C. Tuberculosis. Lancet 2003; 362: 887–899.
2 World Health Organization. Global tuberculosis control—
surveillance, planning, financing. WHO/HTM/TB/2008.393.
Geneva, Switzerland: WHO, 2008.
3 Sharma S K, Mohan A. Extra-pulmonary tuberculosis. Indian J
Med Res 2004; 120: 316–353.
4 Sharma S K, Mohan A, Kadhiravan T. HIV-TB co-infection:
epidemiology, diagnosis and management. Indian J Med Res
2005; 121: 550–567.
5 Sonnenberg P, Glynn J R, Fielding K, Murray J, Godfrey-Faussett
P, Shearer S. HIV and pulmonary tuberculosis: the impact goes
beyond those infected with HIV. AIDS 2004; 18: 657–662.
6 Perkins M D, Cunningham J. Facing the crisis: improving the
diagnosis of tuberculosis in the HIV era. J Infect Dis 2007; 196
(Suppl 1): S15–S27.
7 Godfrey-Faussett P, Kaunda H, Kamanga J, et al. Why do patients with a cough delay seeking care at Lusaka urban health
centres? A health systems research approach. Int J Tuberc Lung
Dis 2002; 6: 796–805.
8 Harries A D, Nyirenda T D, Godfrey-Faussett P, Salaniponi F M.
Defining and assessing the maximum number of visits patients
should make to a health facility to obtain a diagnosis of pulmonary tuberculosis. Int J Tuberc Lung Dis 2003; 7: 953–958.
9 Harries A D, Hargreaves N J, Gausi F, Kwanjana J H, Salaniponi F M. High early death rate in tuberculosis patients in Malawi. Int J Tuberc Lung Dis 2001; 5: 1000–1005.
10 Needham D M, Godfrey-Faussett P, Foster S D. Barriers to tuberculosis control in urban Zambia: the economic impact and
burden on patients prior to diagnosis. Int J Tuberc Lung Dis
1998; 2: 811–817.
744
The International Journal of Tuberculosis and Lung Disease
11 Needham D M, Foster S D, Tomlinson G, Godfrey-Faussett P.
Socio-economic, gender and health service factors affecting diagnostic delay for tuberculosis patients in urban Zambia. Trop
Med Int Health 2001; 6: 256–259.
12 Siddiqi K, Lambert M L, Walley J. Clinical diagnosis of smearnegative pulmonary tuberculosis in low-income countries: the
current evidence. Lancet Infect Dis 2003; 3: 288–296.
13 Getahun H, Harrington M, O’Brien R, Nunn P. Diagnosis of
smear-negative pulmonary tuberculosis in people with HIV infection or AIDS in resource-constrained settings: informing urgent policy changes. Lancet 2007; 369: 2042–2049.
14 Meintjes G, Schoeman H, Morroni C, Wilson D, Maartens G.
Patient and provider delay in tuberculosis suspects from communities with a high HIV prevalence in South Africa: a crosssectional study. BMC Infect Dis 2008; 8: 72–79.
15 Lorent N, Mugwaneza P, Mugabekazi J, et al. Risk factors for
delay in the diagnosis and treatment of tuberculosis at a referral hospital in Rwanda. Int J Tuberc Lung Dis 2008; 12: 392–
396.
16 Ojikutu B, Makadzange A T, Gaolathe T. Scaling up ART treatment capacity: lessons learned from South Africa, Zimbabwe,
and Botswana. Curr HIV/AIDS Rep 2008; 5: 94–98.
RÉSUMÉ
C O N T E X T E : Patients adultes atteints de tuberculose (TB)
et recrutés entre 2003 et 2004 à la Clinique Thoracique
de l’Hôpital d’Enseignement Universitaire de Lusaka,
Zambie.
O B J E C T I F : Identifier les facteurs en association avec un
retard de traitement ou d’hospitalisation.
S C H É M A : Enquête transversale chez les patients adultes
récemment identifiés comme atteints de TB.
R É S U LTAT S : On a inclus 223 patients dans l’analyse. Le
risque d’hospitalisation est 2,6 fois supérieur chez les patients atteints d’une maladie à bacilloscopie négative des
frottis par rapport à ceux à bacilloscopie positive (IC95%
1,28–5,30) ; le risque d’hospitalisation est 3,42 fois supérieur chez les patients atteints de maladie extrapulmonaire par rapport à ceux atteints de maladie pulmonaire
(IC95% 1,75–6,66). Le risque de délai global est 2,81
fois plus élevé chez les patients atteints de maladie à bacilloscopie négative des frottis par rapport à ceux atteints
de maladie à bacilloscopie positive (IC95% 1,20–6,66).
D I S C U S S I O N : Cette analyse a démontré que les patients
atteints d’une maladie extrapulmonaire ou à bacilloscopie négative des frottis sont significativement plus susceptibles d’être hospitalisés. En plus, les patients atteints
d’une maladie à bacilloscopie négative sont plus susceptibles d’avoir subi un retard de traitement. Ces données
renforcent la nécessité urgente de disposer de tests plus robustes de diagnostic, particulièrement pour les maladies
à bacilloscopie négative ou extrapulmonaires. Comme
ces formes de maladie sont plus susceptibles d’être en
association avec le virus de l’immunodéficience humaine
(VIH), ces données plaident en faveur d’un diagnostic et
d’un traitement plus précoces de l’infection VIH.
RESUMEN
M A R C O D E R E F E R E N C I A : Los pacientes adultos con tuberculosis (TB) que acudieron a la consulta de neumología en el Hospital Universitario de Lusaka, en Zambia,
entre el 2003 y el 2004.
O B J E T I V O : Definir los factores asociados con el retraso
en el tratamiento antituberculoso y la hospitalización.
M É T O D O S : Fue este un estudio transversal de pacientes
adultos con diagnóstico reciente de TB.
R E S U LTA D O S : En el análisis se incluyeron 223 pacientes.
La probabilidad de hospitalización fue 2,6 veces mayor
en los pacientes con baciloscopia negativa que en los pacientes con baciloscopia positiva (IC95% 1,28–5,30) y
3,42 veces mayor en los pacientes con enfermedad extrapulmonar que en los pacientes con TB pulmonar (IC95%
1,75–6,66). El retraso del tratamiento en los pacientes
con baciloscopia negativa fue 2,81 veces más probable
que en los pacientes con baciloscopia positiva (IC95%
1,20–6,66).
C O N C L U S I Ó N : En este análisis se demostró que los pacientes con TB extrapulmonar o baciloscopia negativa
presentaban una probabilidad significativamente mayor
de hospitalización. Además, en los pacientes con TB y
baciloscopia negativa se observó una mayor probabilidad
de retraso en el comienzo del tratamiento. Estos datos
confirman la urgente necesidad de métodos diagnósticos
eficaces, sobre todo en los casos de TB con baciloscopia
negativa y TB extrapulmonar. Dado que estas formas
clínicas son más frecuentes en las personas con infección por el virus de la inmunodeficiencia humana, estos
resultados subrayan la importancia del diagnóstico temprano y el tratamiento oportuno de la infección por este
virus.