Previous assumptions about the diagnosis of TB in HIV-infected people may need to be revised, according to findings from a Tanzanian study suggesting that a significant minority of HIV-positive people have active and in some cases potentially infectious tuberculosis, without any symptoms or indications of active TB in a sputum test.
It is well established that HIV infection can make it hard to diagnose cases of tuberculosis (TB). TB skin tests and sputum smears are often negative despite active infection, and chest X-rays cannot distinguish TB from other ailments common in people with HIV. But these are usually problems related to proving that TB is the cause of apparent symptoms such as a fever or persistent cough.
A paper in the current issue of the journal Clinical Infectious Diseases focuses on another confounding aspect of TB and HIV management. In the paper, researchers screening people living with HIV for a TB vaccine study in Tanzania were surprised to discover a high rate of unrecognised and sometimes even subclinical TB cases without persistent coughing or other obvious symptoms. Their findings suggest that people living with HIV in areas with a high burden of TB may commonly harbour silent and unrecognised, yet active, TB infections that may only be detected by proactive screening.
Still, just because symptoms are not noticeable it does not mean these cases are harmless. In fact, the consequences could be quite serious if patients start their treatment with either TB prophylaxis or antiretroviral therapy (ART).
TB and HIV coinfection
In the developing world TB is the leading cause of death among people with HIV infection. Efforts to control the disease are failing in regions where HIV infection is common, particularly in sub-Saharan Africa, partly because advanced HIV disease foils the standard tests used to diagnose TB.
TB control efforts are based upon isoniazid (INH) treatment to keep latent infections from becoming active, and combination therapy to cure infectious pulmonary TB. But latent infections must first be diagnosed with skin tests based on an immune response to TB antigens which is often absent in patients with advanced immune suppression.
When the skin tests are positive, it is important to rule out active disease before starting INH prophylaxis. However, it can be difficult to rule out active infection in people with HIV. Sputum smear microscopy, the primary diagnostic test for active (and infectious) tuberculosis, involves looking for TB microbes (acid-fast bacilli/AFBs) in a dye-treated sputum sample under a microscope. However, this method cannot detect TB that has spread from the lungs to other parts of the body, which is a common complication in people with HIV.
At best smear microscopy can detect around 45-60% of people who have active TB wherever HIV coinfection is prevalent. If smears are negative, it may still be possible to find active TB by sending a specimen out to the regional reference laboratory for ‘culturing.’ Culturing shows whether there is mycobacterium that can be grown out and isolated in a sample — a process that can take more than a month in most resource limited settings.
The difficulty in diagnosing active TB has led some healthcare providers to ignore a WHO recommendation to treat smear negative latent TB infections with INH prophylaxis. According to a Médecins Sans Frontières's (MSF) report last year, “MSF programmes generally do not implement this recommendation because there is no way of knowing whether an asymptomatic smear-negative HIV positive patient has active TB, latent TB or no TB at all, and administering prophylaxis could create drug resistance". (see online http://www.accessmed-msf.org/documents/FINAL RUNNING OUT OF BREATH 210305.pdf.)
Tanzanian TB test
MSF’s concerns appear to be corroborated by the Tanzanian findings. The researchers, looking for potential participants for a TB vaccine study in Dar es Salaam, were recruiting only HIV positive adults with CD4 cell counts of 200 cells/mm3 or over, and without active tuberculosis. But identifying patients with active TB proved more difficult than the investigators had anticipated.
Screening included a physical examination and a standardised interview with questions about weight loss in the past three months, and about the presence and duration of any cough or fever. TB skin tests were also performed to check for TB exposure.
Patients with positive TB skin tests were then screened for active TB with chest x-rays, sputum smear microscopy and culturing (either of sputum or blood), and laboratory tests were conducted looking for immunologic reactions to TB in a sample of the patient’s blood.
Of the first 93 HIV positive adults screened with CD4 cell counts over 200 cells/mm3, 14 were found to have active TB. Four of these cases had no symptoms (subclinical TB). At this point of the study, researchers decided to exclude any patient when there was even the slightest suspicion of TB. Despite this, six of 407 more patients deemed eligible for the study were subsequently determined to have subclinical TB at baseline on the basis of positive sputum culture results.
Characteristics of unrecognised TB
The researchers then decided to take a closer look at the cases of active TB. Even the cases with some clinical evidence of TB were difficult to diagnose. Only five had a cough or fever lasting more than two weeks. Seven had chest x-rays suggestive of TB, but again these findings were not considered definitive. Only two had both chest x-rays and symptoms suggestive of TB. Most had positive skin tests but sputum smears were negative in all of these patients. Culturing, the gold standard of diagnosis, only detected TB in two of these cases. Nevertheless, investigators concluded that seven patients had a definite or probable TB, and the other three were categorised as “possible” TB cases.
But culturing detected TB in all ten cases of subclinical TB even though there were no signs, symptoms, or abnormal chest X-ray findings suggestive of active tuberculosis. Indeed, culturing was the only clue to TB in most of these patients. Only one had a sputum smear that was positive — although specimens from two were found to be positive upon re-examination (only after they were found to be culture-positive). Two patients reported a cough of less than a week’s duration which is too brief a period to suggest TB.
The researchers conducted a variety of specialised laboratory assessments which indicated that the infections were due to genuine invasive infections, and not due to contamination in the laboratory or transient colonization. One of these laboratory assessments consistently found immune responses in the patient’s blood to a M. tuberculosis protein called ESAT-6. “These findings raise the possibility of an immunodiagnostic approach to early diagnosis of subclinical tuberculosis,” said the researchers.
One potentially useful finding for screening was that, compared with the patients without TB, those with subclinical cases were more likely to have mildly swollen lymph nodes and positive TB skin tests. In fact, six out of ten of the patients with subclinical TB had lympha-denopathy and skin test reactions larger than 10mm. Only four out of over four hundred patients without these findings had subclinical TB.
Previous reports have emphasised that patients with advanced HIV infection may have unusual presentations of active tuberculosis, which can be hard to diagnose. This study identified a syndrome of subclinical tuberculosis in HIV positive individuals with CD4 cell counts of more than 200 cells/mm3. According to the researchers, this “ pattern... of sputum culture–positive subclinical tuberculosis in HIV-infected patients, without [symptoms or x-ray] features of tuberculosis, has, to our knowledge, not been described previously.”
The findings have significant implications for TB and HIV management in areas where coinfection is common.
One possible ramification is that greater care should be taken before initiating INH prophylaxis in patients with positive skin test results. It may be advisable to wait until culture results become available because under-treatment of a subclinical active case could lead to drug resistance.
It is important to note that, in this study, most of the patients with subclinical TB were put on INH prophylaxis for 14 weeks before their cultures came back positive and therapy was switched to multiple-drug treatment for active tuberculosis. Even though all of the subjects in the study had negative sputum culture results after receiving INH, some experienced progression of symptoms during or after INH monotherapy. However, they responded well to the subsequent combination TB therapy.
Another danger with subclinical TB is that if it is not recognised and treated before a patient eventually begins antiretroviral therapy, the individual could develop the potentially serious immune restoration inflammatory syndrome (IRIS) (see http://www.aidsmap.com/en/news/F58C2D55-262E-4DD0-A5D6-10BAA73B663F.asp , and HATIP issue on IRIS).
It isn’t clear whether, or how often, patients with subclinical TB infection are infectious, but since at least a few were sputum test positive (a sign of infectiousness), it is possible that these patients represent an unrecognised source of transmission not currently being reached by TB control efforts.
In regions where HIV and TB coinfection is common, waiting until people develop a cough or fever before screening them for TB may be too late. As stressed in an editorial accompanying the Tanzanian study: “The solution to the enormous problem of two interrelated and overlapping epidemics will rely on increased collaboration and coordination between tu-berculosis-control and AIDS-control programs, [and] enhanced detection of both tuberculosis and HIV infection.”
Cohn DL. Subclinical tuberculosis in HIV-infected patients: another challenge for the diagnosis of tuberculosis in high-burden countries? Clinical Infectious Diseases 40(10):1508-10, 2005.
Mtei L et al. High rates of clinical and subclinical tuberculosis among HIV-infected am-bulatory subjects in Tanzania. Clinical Infectious Diseases 40(10):1500-7, 2005.