The four-symptom screen for active tuberculosis (TB) that is
recommended for all people living with HIV in lower-income settings is less
likely to detect active TB in people taking antiretroviral therapy (ART) and
may be improved by the additional use of a chest x-ray, according to a systematic review and
meta-analysis by the World Health Organization.

The findings are published in the journal The Lancet HIV.

Tuberculosis remains the biggest cause of death in people
living with HIV, including those already taking antiretroviral therapy. The
World Health Organization estimated that nearly 400,000 people with HIV died of
TB in 2016. Preventing the development of active tuberculosis by giving
isoniazid preventive treatment is a priority for reducing the incidence of TB
in people living with HIV. TB prevention using isoniazid requires screening to
rule out active TB, as the use of isoniazid preventive therapy in a person with
active TB would lead to the development of isoniazid resistance.

To improve the uptake of isoniazid preventive treatment, the
World Health Organization developed a four-symptom screening test that allows
physicians to rule out the presence of active TB. In the absence of current
cough, weight loss, night sweats or fever, TB preventive treatment can be
started. If any of the symptoms is present, further investigation is necessary.

A meta-analysis showed that this four-symptom screen had a
sensitivity of 79% and a specificity of 50% (in other words, the screen would correctly
identify active TB in 79% of people who had it and correctly rule out active TB
in 50% of people who do not have TB).

However, the four-symptom screen appears less sensitive in
people on antiretroviral therapy, missing more cases of active TB than in
people not on ART. To determine the sensitivity and specificity of the
four-symptom screen in people on ART and to establish whether the use of a chest
X-ray would improve the sensitivity of screening in people on ART, the World
Health Organization carried out a systematic review of studies and a
meta-analysis of study data.

The systematic review looked for studies published in journals or presented at conferences after the
WHO recommended the four-symptom screen in 2011,
in which the sensitivity and specificity of the four-symptom screen was
verified with sputum or other samples, tested using culture or Xpert MTB/RIF.

The review identified 21 prospective cohort studies
involving 15,247 people with HIV. Ten studies included people taking ART but three
studies were excluded from the meta-analysis because they did not disaggregate
data according to ART status.

The meta-analysis covered 18 studies involving 4,640 people
taking ART and 8,664 people who were previously untreated at baseline. A median
of 68% of people with HIV had at least one of the four symptoms but the median
proportion of people on ART who had at least one symptom was lower, at 29.7%.

The meta-analysis found a pooled sensitivity of the
four-symptom screen in people on ART of 51% (95% CI 28.4-73.2) – that is to
say, the screen would identify only half of the people on ART who had active
TB. The specificity was 70.7% (95% CI 47.8-86.4%). In treatment-naïve people,
sensitivity was much higher in the pooled analysis (89.4%, 95% CI 83-93.4%),
but specificity was lower (28.1%, 95% CI 18.6-40.1%) than in ART-treated
people. However, when studies reporting no active TB in people not on ART were
excluded, sensitivity improved in people on ART (62.1%, 95% CI 38.4-81.1%) but
was almost unchanged in treatment-naïve people (88.5%, 95% CI 55-98).

Sensitivity of the four-symptom screen in people on ART was
higher in studies that did not include pregnant women (62.1%, 95% CI
38.4-81.1%) but specificity was lower (62.9%, 33.2-85.3%).

Five studies included data on chest x-ray findings. However, only
two studies provided data on 646 patients that allowed the pooled sensitivity
and specificity of the four-symptom screen plus chest x-ray to be calculated in
people on ART.

These two studies suggested that adding the chest x-ray improved the sensitivity (84.6%, 95% CI 69.7-92.9%) but also substantially lowered the specificity (29.8%, 95% CI

The review authors say that the four-symptom screen may be
less sensitive in people on ART because people with low CD4 counts – more
likely to be initiating ART – are also more likely to present with symptoms of
fever or weight loss due to HIV disease or other opportunistic infections. 

Although chest x-ray significantly improved the sensitivity
of screening in people on ART, the authors of an accompanying comment article,
Colleen Hanrahan and David Dowdy of the Johns Hopkins Bloomberg School of
Public Health, question whether the modest improvement in the probability of
detecting active TB in the absence of symptoms is worth the logistical and
financial challenges that national treatment programmes will face if they try to expand the use of chest x-ray.

“It is likely that a recommendation to require chest x-ray
before initiation of preventive therapy will do more harm than good,” they say,
pointing out that the reduction in the specificity of the four-symptom screen
if chest x-ray is added would reduce the number of people eligible for
isoniazid preventive treatment.

In the light of these findings, the World Health
Organization has recommended that chest x-ray may be added to the four-symptom
screen in people who have already started ART.