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Diagnosis and reasoning

This patient has presented with a fever of unknown origin (FUO), in association with a cough and constitutional symptoms; examination reveals the presence of crackles and bronchial breathing in the right apex. These clinical findings are strongly suspicious of pulmonary tuberculosis (PTB), which is the commonest cause of FUO; note also that the disease is more common in individuals with a disadvantaged socioeconomic background. While several other respiratory diseases (such as atypical pneumonias, lung abscesses and sarcoidosis) can also present in a similar manner, these are probably best considered if and when PTB has been excluded. A chest x-ray is a good initial investigation here; this shows a cavitary lesion in the right apex, which is further supportive of PTB. However, his sputum smears turn out to be negative, while at 6 mm, his tuberculin test also appears to be negative. Could this be a different etiology ? At this point, it is important to note that all patients who present with signs or symptoms suggestive of TB should be screened for HIV. This is important because active TB in an HIV patient is an AIDS defining illness, and also because the presence of HIV affects how one interprets certain investigations. In this patient, HIV serology turns out to be positive - even though he denies unsafe sexual contact or blood transfusions. Note also that an induration > 5 mm in the tuberculin test is considered positive in HIV-infected individuals; in addition, HIV infected PTB patients are often smear negative. Thus, according to current WHO guidelines, this patient may be classified as a smear-negative PTB case, as he shows radiographic abnormalities consistent with active PTB and has laboratory evidence of HIV infection. The WHO also recommends that TB treatment should be started first, followed by anti-retroviral treatment (ART) as soon as possible and within the first 8 weeks of starting TB treatment; the rationale is that case-fatality among HIV/TB patients occurs mainly in the first 2 months of TB treatment. The cons of this approach are having a large number of tablets to ingest, which may discourage treatment adherence and an increased incidence of adverse effects, drug-drug interactions and immune reconstitution inflammatory syndrome (IRIS). Note that ART should be initiated for all people living with HIV with active TB disease irrespective of CD4 cell count. Preventive therapy with Co-trimoxazole should be started in these patients as soon as possible, as it reduces mortality substantially (possibly due to preventing Pneumocystis jirovecii and a range of bacterial infections). As this patient's sputum is free of bacilli, he need not be isolated.


The HIV/AIDS epidemic has contributed to a significant increase in the worldwide incidence of tuberculosis; approximately 10 million people are estimated to be coinfected with M tuberculosis and HIV, with over 90% of these individuals residing in developing nations. Worldwide, tuberculosis is the most common cause of death among patients with AIDS, killing 1 in every 3 patients. In patients infected with HIV, chest x-ray appearances are often non-specific, symptoms and signs may not be classical and the sputum may be negative on a direct smear; they are also more likely to present with extrapulmonary TB. These individuals should receive daily TB treatment during both the intensive and continuation phases. The treatment of HIV-related tuberculosis requires close monitoring because of frequent drug toxicities, possible drug-drug interactions, and paradoxical reactions (i.e. temporary exacerbation of symptoms, signs, or radiographic manifestations of TB while receiving anti-TB treatment).

Take home messages

  1. Active TB in a HIV patient is an AIDS defining illness.
  2. In newly diagnosed HIV/TB patients, start TB treatment first, followed by ART soon afterward (within the first 8 weeks).
  3. ART should be initiated in all HIV positive individuals with active TB, irrespective of CD4 cell count.
  4. Co-trimoxazole preventive therapy should be commenced in all HIV/TB patients.

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  1. Am Fam Physician. 2003 Dec 1;68(11):2223-2229, Approach to the Adult Patient with Fever of Unknown Origin, Alan R. Roth, D.O., and Gina M. Basello, D.O.
  2. BMJ 2006; 332 doi: (Published 18 May 2006),Pulmonary tuberculosis: diagnosis and treatment.
  3. MMWR Recomm Rep. 2003 Jun 20;52(RR-11):1-77, Treatment of tuberculosis, American Thoracic Society; CDC; Infectious Diseases Society of America.
  4. Proc Am Thorac Soc. 2011 June 1; 8(3): 288–293, doi: 10.1513/pats.201010-064WR, Epidemiology of Tuberculosis and HIV, Recent Advances in Understanding and Responses,Neil A. Martinson, Christopher J. Hoffmann,and Richard E. Chaisson.
  5. Treatment of Tuberculosis: Guidelines, 4th edition, Geneva: World Health Organization; 2010, ISBN-13: 978-92-4-154783-3.