Updates
by Carol A. Kemper, MD, FACP
Difficulties in Diagnosing Intestinal TB
Source: Martinez Tirado P, et al. Gastroenterol Hepatol. 2003;26:351-354.
An elderly man with underlying myasthenia gravis presented to the hospital with 8 months of progressive weakness and a 30-lb weight loss. He described 2-3 weeks of increasing headache, visual disturbance, and left lower quadrant pain. He had been maintained on prednisone and intermittent use of Imuran for about 5 years. The progressive weakness, which was initially attributed to the myasthenia, had been treated with increasing doses of prednisone (60 mg per day). Evaluation revealed cryptococcal meningitis and a 5-cm left pelvic abscess, which appeared to be diverticular in origin. Aspirates of the abscess material showed numerous acid-fast bacilli. Both stool and abscess material grew a mycobacterium, but cultures were contaminated with bacterial flora and identification was not possible. Chest radiographs were unremarkable; the patient had no significant respiratory symptoms and was unable to produce sputum for culture. A bone marrow biopsy showed no evidence of granuloma, and mycobacterial cultures were negative. Although colonoscopy was not performed, the gastroenterologist believed he had diverticulitis with abscess formation and assumed the mycobacterium was a contaminant.
The man had a remote history of exposure to a brother-in-law with TB in the 1950s. He had never been tested for latent TB. Would you treat for TB?
The diagnosis of intestinal TB can be tricky, especially in immunosuppressed patients in whom the presentation is atypical. Gastroenterologists may be unfamiliar with the diagnosis and the presentation at colonoscopy, which can resemble Crohn’s disease or diverticulitis. Intestinal TB commonly manifests as circular inflammatory ulcers, small diverticuli (3-5 mm), or firm sessile polypoid-appearing lesions that may be mistaken for polyps. Endoscopic biopsies usually demonstrate caseating granuloma formation and acid-fast stains are often positive, although granuloma formation may be deceptively poor in an immunosuppressed host.
This case offers several important points: (1) Patients receiving immunosuppressive agents should be screened for latent TB; (2) Nonpulmonary TB should be considered in any immunosuppressed patient with unexplained weight loss; (3) Although this patient had been receiving immunosuppressives for about 5 years, there is no evidence that the risk of reactivation TB decreases over time; thus, he was just as much at risk for reactivation TB as he ever was; (4) Intestinal TB may be mistaken for Crohn’s disease or diverticulitis, but biopsies and cultures are often diagnostic.
Can Human Betaretroviruses Trigger Autoimmune Disease?
Source: Xu L, et al. Proc Natl Acad Sci USA. 2003;100:8454-8459.
Researchers have long suspected a viral trigger in the development of primary biliary cirrhosis (PBC), an autoimmune disease somewhat related to Sjogren’s and associated with the development of antimitochondrial antibodies and destruction of small intrahepatic bile ducts. Xu and associates were able to visualize viral particles in biliary epithelium and extract retroviral nucleotide sequences similar to known betaretroviruses, including murine mammary tumor virus and retroviral sequences found in human breast cancers.
Previous attempts by Xu et al to identify a specific virus in a patient with PBC led to the isolation of several human endogenous retrovirus sequences, but none were clearly associated with the development of autoimmune disease. Based on reports of identification of a possible retrovirus in patients with Sjogren’s, called human intracisternal A-type particle, Xu et al developed a PCR primer based on the retroviral pol sequence and were able to clone exogenous nucleotide sequences from several patients with PBC. Using biliary epithelium cells obtained from 3 patients with PBC, a 125-bp PCR product was obtained, from which 8 different clones were sequenced. The clones had 97% homology with each other. A search of viral nucleotide sequences revealed a 95-97% homology with multiple murine mammary tumor virus pol genes and 95% similarity to a human retroviral pol gene cloned from breast cancer tissue. Similar relatedness was observed when comparing viral env genes from these various viruses.
Using electron microscopy, extracellular mature retrovirus (100-120 nm) was visualized in 3 patients with PBC, but only 1 similar particle was found in liver samples taken from 5 patients with other liver disease. However, the viral burden appeared to be fairly low, with viral particles detected in only about 1:100 cells from patients with PBC. Human betaretrovirus cDNA was also detected from 73% of perihepatic lymph nodes from patients with PBC vs 20% of control subjects, suggesting that perihepatic lymph nodes may serve as a reservoir for viral replication and not hepatic cells per se.
Xu et al were also able to co-culture normal biliary epithelium cells with extracts of liver transplant tissue from patients with PBC and demonstrate induction of the PBC phenotype in those cells, with evidence of reverse transcriptase activity. This finding lends support for the hypothesis that this human betaretrovirus acts as a trigger for PBC, although the virus has not been isolated in culture, and it remains unknown whether this virus is present in all cases of PBC. In addition, this betaretroviral infection may be significantly more common than the development of PBC (which clusters in families and occurs in about 1 in 50,000 individuals in Northern Europe and America), suggesting that the virus may act as a trigger only in genetically susceptible patients. Pilot studies are ongoing to examine whether patients with PBC respond to antiretroviral therapy, such as lamivudine and zidovudine.
Rifampin and Pyrazinamide No Longer Recommended for Latent TB
Source: MMWR Morb Mortal Wkly Rep. August 8, 2003. http://www.cdc.gov/mmwr.
Following a review of hepatic injury in patients receiving a 2-month regimen of rifampin and pyrazinamide for latent tuberculosis, the American Thoracic Society (ATS) and the CDC decided to reverse their original recommendation and advised against the general use of this combination for the treatment of latent TB.
In the 1990s, preliminary data in patients with HIV infection suggested that a 2-month course of rifampin and pyrazinamide was both safe and effective and helped to limit some of the adverse pharmacokinetic interactions of rifampin and the antiretroviral drugs. Based on those data, in April 2000, the ATS and CDC included this regimen was an alternative to isoniazid (INH). Unfortunately, in October 2000, the CDC received a report of a death in a patient receiving this combination. Since then, the CDC has collected data on 48 cases of severe hepatic injury in patients receiving this regimen, including 11 deaths (2 of whom were HIV infected). This rate of injury and death is both unexpected and inexplicably greater than that found in patients receiving rifampin and pyrazinamide in multidrug regimens for treatment of active TB.
Treatment of latent TB is still encouraged for any patient with a positive PPD, irrespective of age or a history of BCG vaccination. The preferred regimen remains INH for 9 months; alternatives include INH for 6 months or rifampin for 4 months. The current caution against the general use of the rifampin/pyrazinamide regimen for treatment of latent TB does not apply to the use of multidrug regimens for the treatment of active TB.
Meningitis in Children with Cochlear Implants
Sources: FDA Public Health Web Notification. Updated July 31, 2003; Reefhuis J, et al. N Engl J Med. 2003; 349:435-445.
The FDA first issued a public health advisory in July 2002 regarding a possible association between cochlear implants in children and bacterial meningitis and requested information regarding additional cases.* Cochlear implants are that novel new technology that allows activation of auditory nerve fibers via electrodes implanted in the inner ear. An estimated 60,000 individuals worldwide have been implanted with the devices. Since that original article, the FDA/CDC has reviewed the medical records of 4264 children who had received implants before 6 years of age. The study focused on children with implants because they are the major recipients of these devices and have accounted for the majority of known meningitis cases. Twenty-six (0.7%) had developed meningitis, the majority of which were due to Streptococcus pneumoniae. Interestingly, the study suggested that implants with electrode positioners were more common in children with meningitis than implants without positioners, although the basis for this is not understood.
A separate FDA review of 69 cases of implant-associated meningitis also found that S pneumoniae was the most common infectious agent identified (46 cases), followed by Haemophilus influenzae (9 cases), Escherichia coli (4 cases), S viridans (3 cases), Staphylococcus spp. (4 cases), and other nonspecified bacteria (4 cases). Based on these findings, the FDA is strongly encouraging appropriate vaccination of cochlear implant candidates with pneumococcal conjugate vaccine or polysaccharide vaccine, as well as Haemophilus B conjugate vaccine. Clinicians should be aware that, despite vaccination, 2 implant patients developed pneumococcal meningitis and 2 developed H influenzae meningitis. Clinicians should therefore aggressively treat all middle-ear infections in these patients and train the families of cochlear implant patients to recognize early symptoms of meningitis.
*Kemper CA. Infectious Disease Alert. 2002;21:168.
Difficulties in Diagnosing Intestinal TB; Can Human Betaretroviruses Trigger Autoimmune Disease?; Rifampin and Pyrazinamide No Longer Recommended for Latent TB; Meningitis in Children with Cochlear ImplantsYou have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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