WHO releases revised guidelines for diagnosis of smear negative and extrapulmonary TB in HIV-prevalent settings

This article is more than 18 years old. Click here for more recent articles on this topic

When someone with a suspected case of TB is dangerously ill, in particular a person with HIV, ‘flexibility’ may be needed when making the diagnosis, according to recommendations just released by the World Health Organization (WHO). The new guidelines revise previously used algorithms in an effort to speed up the diagnosis of smear-negative pulmonary and extrapulmonary TB in resource-limited settings wherever HIV is prevalent.

Revised clinical definitions of TB

But given the strong association of HIV and TB, the new WHO recommendations lower the bar somewhat for what evidence is required to diagnose TB in someone with HIV who has the symptoms of TB. For example, WHO typically recommends performing smear microscopy on three sputum samples for anyone one with a cough for two or three weeks, and if two of the specimens are positive, a diagnosis of pulmonary TB can be made.

Now, however, WHO suggests acquiring only two sputum specimens for smear microscopy from someone who is HIV-infected (or when there is strong clinical evidence of his or her being HIV-infected). This should reduce the time (and repeated visits the patient has to make to the clinic) required to make a diagnosis. If one of the specimens is positive, a diagnosis of pulmonary TB can be made.

Problems diagnosing TB in people with HIV

In people with HIV, TB can be exceedingly difficult to detect by the usual methods, such as smear microscopy and chest x-rays. Smear microscopy involves using a microscope to look for the actual Mycobacterium tuberculosis (M.tb) organism in a sample of sputum (or other biological specimen) that has been stained with a special dye — but specimens from people with HIV and TB are frequently ‘smear negative.’



A specimen of tissue or other material taken from part of the body and smeared onto a microscope slide for examination. A Pap smear is a specimen of material scraped from the cervix (neck of the uterus) examined for precancerous changes.


Affecting the lungs.



Antibiotics, also known as antibacterials, are medications that destroy or slow down the growth of bacteria. They are used to treat diseases caused by bacteria.


In a bacteria culture test, a sample of urine, blood, sputum or another substance is taken from the patient. The cells are put in a specific environment in a laboratory to encourage cell growth and to allow the specific type of bacteria to be identified. Culture can be used to identify the TB bacteria, but is a more complex, slow and expensive method than others.


Material coughed up from the lungs, which can be examined to help with diagnosis and management of respiratory diseases.

Likewise, chest x-rays, if available, may look normal or not like TB in a person with HIV and TB, while many people with HIV develop extrapulmonary forms of the disease. Culturing the organism can usually provide a definitive diagnosis, but culturing takes weeks, and is not commonly available for many people in resource-limited settings.

“Rates of smear-negative pulmonary and extrapulmonary tuberculosis have been rising in countries with HIV epidemics,” says the WHO document. “The mortality rate among HIV-infected tuberculosis patients is higher than that of noninfected tuberculosis patients, particularly for those with smear-negative pulmonary and extrapulmonary tuberculosis.”

The delay in diagnosis, and the resulting delay in treatment, contribute to this increased mortality.

Antibiotics trial in the dangerously ill patient

However, smear microscopy and chest x-rays may not pick up TB in some patients who are too ill to wait the weeks or months that it might take to get a culture result back from the reference laboratory. There are several ‘danger signs’ that indicate a need for emergency measures, including if the person is inable to walk unaided, has a respiratory rate over 30 per minute, a fever higher than 39 °C or a pulse rate of over 120 per minute.

In cases where someone is this dangerously ill but the diagnosis is unclear or cannot be reached rapidly enough, the new WHO recommendations suggest sending the person as quickly as possible a higher-level facility. If that isn’t possible, then the person should be immediately put on a broad-spectrum parenteral antibiotic, and, depending upon the CD4 cell counts or clinical setting, treatment for Pneumocystis pneumonia (PCP, also known as Pneumocystis jirovecii pneumonia) should be considered as well.

At this time, WHO says that there isn’t enough clinical evidence to make any broad recommendations about which specific antibiotics would be best to use (this should be perhaps guided by what works best locally to treat community acquired bacteria infections), however, fluoroquinolones should NOT be administered because this class of drugs has activity against M.tb, and thus could delay TB diagnosis.

Then for the next few days while the patient is on antibiotic therapy, all available lab tests (including an HIV test) should be conducted. If the patient is indeed HIV-positive and there is no clinical improvement after three to five days on the antibiotics, chances are the person has smear negative TB, and he or she should be put on tuberculosis treatment. However, the guidelines point out that people should continue to be assessed for TB, even if there is a response to antibiotics (since there could be a coinfection, or some antibiotics may have mild — but not curative —anti-TB activity).

Smear-negative pulmonary TB

If both the specimens are smear negative, but a chest x-ray (if available) suggests TB, a diagnosis of smear-negative TB can be made if the clinician decides to treat with a full course of TB treatment and monitor closely for the response (that would a signal that the finding was correct). In addition, a diagnosis of smear-negative TB can be reached once a specimen sent for culture comes back positive for M. tb.

Extrapulmonary TB

Healthcare workers at all levels need to be on the lookout for extrapulmonary TB in people with HIV. In addition to a cough (which may or may not be present), a variety of symptoms, fevers with night sweats, weight loss, difficulty breathing, swollen lymph nodes, or swollen arms and legs, or a chronic headache or altered mental state could all be suggestive of TB in another part of the body.

Extrapulmonary TB can take such a wide variety of forms because in a person with advanced immunosuppression, the mycobacterium can infect tissues in almost any part of the body. The most common areas include the lymph nodes (especially in the neck or under the arms), the pleura (the membrane that lines the lungs and chest cavity — though usually just one side is infected) and disseminated tuberculosis (spread to a number of sites in the body). M.tb can also infect the tissue around the heart, or the meninges (the membranes covering the brain and spinal cord) and other areas.

But it is important to note that extrapulmonary TB is even more commonly associated with HIV status than smear negative pulmonary TB, so learning the patient’s HIV status is all the more essential for a diagnosis. According to the WHO document, “about one-third of deaths in HIV-positive Africans are due to disseminated tuberculosis but only about half of HIV-positive patients who die from disseminated tuberculosis are diagnosed before death.”

The revised definition of extrapulmonary TB requires obtaining a positive result, by smear microscopy or culture, on at least one biological specimen from the site of infection. Or, a diagnosis may be made if there is histological or strong clinical evidence consistent with extrapulmonary TB in a person with (or strongly suspected of having) HIV, and a decision to treat with a full course of anti-TB treatment.

Acquiring a good specimen from the site of infection may be difficult with the exception perhaps of TB lymphadenitis (needle aspiration of lymph nodes generally produces material with a high diagnostic yield by culture or smear microscopy). Therefore, clinicians often have to make a presumptive diagnosis and initiate TB treatment on the basis of strong clinical evidence alone (and then monitor for a response).

But because the accurate diagnosis of extrapulmonary tuberculosis can be complex and difficult, particularly in peripheral health facilities, referral to the district level is advised whenever possible. Nevertheless, “simplified, standardized clinical management guidelines for most common and serious forms of extrapulmonary tuberculosis” are included in the WHO document (please see link below).

Monitoring the operational effectiveness of the revised guidelines

In some cases, these guidelines are based on expert opinion (and not a strong body of clinical evidence) because of the urgency of responding effectively to TB in HIV prevalent settings. However, WHO recommends that programmes putting the guidelines into practice should monitor the operational effectiveness of these new recommendations.

To make this easier, the document includes a protocol for prospective collection of standardized programmatic data to help make sure that the information gathered can be used to inform changes in policy at national and global levels. For more detailed information, please refer to the document.


Stop TB Department Department of HIV/AIDS, World Health Organisation. Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents. Recommendations for HIV-prevalent and resource-constrained settings. WHO, Geneva, Switzerland, 2006.

See online: http://www.who.int/entity/tb/publications/2006/tbhiv_recommendations.pdf