February 2005

The guest columnist this month is Dan Hale, MD, FAAP, a hospitalist and outpatient pediatrician at the Central Main Medical Center in Lewiston, Maine. He also works as a hospitalist at The Barbara Bush Children’s Hospital in Portland, Maine, the largest children’s hospital in the state. Hale received his MD degree from the University of Wisconsin at Madison in 2000. He then performed his pediatric residency as well as serving as a fourth-year chief resident at The Barbara Bush Children’s Hospital from 2000 to 2004. Hale’s infectious disease consultant on the following case was Carol McCarthy, MD, who was invaluable in guiding the evaluation and treatment of the patient at The Barbara Bush Children’s Hospital.

Case

An 8-year-old Somali girl was admitted to The Barbara Bush Children’s Hospital for evaluation of fatigue and a positive purified protein derivative (PPD). An abnormal chest radiograph (Figures 1 and 2, a close-up of an area in the left lower lobe) revealed a widened mediastinum with adenopathy and abnormalities in the left upper and left lower lobes. The history of her chief complaint was that she had been having worsening fatigue, weakness, occasional emesis, fevers and decreased appetite since arrival in the United States about one month earlier. She had no other complaints, and her past medical history was otherwise unremarkable, being born in Somalia and living in Kenya for several years prior to immigrating to the United States along with her mother and sisters. They were joining her father, who had immigrated to Maine three years previously. She is on no medications and has no allergies. Her immunization status is unknown. She lives with her parents and two siblings, all healthy. There has been no contact with anyone known to have tuberculosis (TB), and both parents and siblings were tuberculin skin test (TST) negative. The patient had a TST placed at the health department at the same time, which measured 25 mm of induration at 48 hours.

Examination on admission revealed a quiet, normal-appearing 8-year-old female, whose vital signs and oxygen saturation were normal. There were no abnormal findings on exam, but chest computed tomography (CT) scan (Figure 3) revealed multiple pulmonary lesions and mediastinal adenopathy with an anterior mass. It also revealed a small cavitation in the left lower lobe (Figure 4). Basic lab tests (electrolytes, complete blood count, urinalysis, liver enzymes and renal function tests) were unremarkable except for her sodium, which was 126 mg/dL. Her HIV, syphilis and hepatitis serologies were negative. Early morning gastric aspirates were obtained for acid-fast stain, which was initially negative, but rare acid-fast bacilli (AFB) were seen on the second sample (hospital day 3) and cultures are pending.

Around the same time, on hospital day 3, she had some spiking fevers to 41°C, ataxia, lethargy and sluggish pupillary response to light. A stat CT scan of the head is shown in Figures 5 and 6, revealing mild hydrocephalus and a lesion at the corpus callosum. This was followed by an MRI shown in Figures 7-10, which again exhibits a large, ring-enhancing lesion at the corpus callosum with surrounding edema. Based on this information, the diagnoses of TB meningitis with a tuberculoma and syndrome of inappropriate antidiuretic hormone (SIADH) were made.

And finally the question: In addition to negative-pressure isolation, fluid restriction for the treatment of SIADH and steroids,

How Would You Initially Treat the TB?

1. Isoniazid, rifampin, pyrazinamide and ethionamide
2. Isoniazid, rifampin and ethambutol
3. Rifampin, ethionamide, gentamicin and pyrazinamide
4. Isoniazid, rifampin, streptomycin and ethionamide

Answer

The gastric aspirate culture grew Mycobacterium tuberculosis, sensitive to all drugs tested. While other combinations may be equally effective, of the choices listed, the only correct answer is A, four-drug therapy with isoniazid (INH), rifampin, pyrazinamide and ethionamide. A series of three early morning gastric aspirates via nasogastric tube is still the simplest method of obtaining reliable specimens. However, in some situations, the patient may be a candidate for bronchoscopy. If so, a bronchoalveolar lavage can be done for AFB stain (Figure 11) and culture with a high rate of success if there is an active pulmonary infection, which is usually the case with extrapulmonary disease.

The diagnosis of TB meningitis with a tuberculoma (rather than abscess) can be made using special MRI spectroscopy technique imaging, combined with the chest radiograph and the gastric aspirate stain and culture. There’s a predilection for this infection to be at the base of the brain (Figure 12 showing an exudative mass of bacilli on autopsy from the Bass collection); therefore, if a patient with meningitis has evidence of cranial nerve involvement, as noted in the patient above, TB should always enter the differential. If cerebrospinal fluid (CSF) is available, it may show a pattern similar to viral meningitis, with a mild to moderate CSF pleocytosis with a predominance of lymphocytes after a brief period of polymorphonuclear leukocyte predominance. The protein and glucose may be normal or elevated/depressed, respectively, depending on how early the CSF is obtained in the course of the illness. Of course, the CSF can be stained and cultured for AFB as well. The gradual onset of symptoms shown in this case is typical for central nervous system (CNS) TB, often extending over several weeks.

Once the diagnosis is made, the management of tuberculous meningitis begins with four antituberculous drug therapies, designed to be a combination of bactericidal and bacteriostatic agents to eliminate the organism and minimize emergence of resistance. Experts typically recommend beginning with INH, rifampin and pyrazinamide (PZA), plus an aminoglycoside or ethionamide. The aminoglycoside recommended is streptomycin. However, this drug may not be readily available, and not all aminoglycosides have reliable activity against M. tuberculosis. According to the Red Book, amikacin, kanamycin or capreomycin (Capastat, Lilly) may be used as alternates. However, kanamycin and capreomycin may not be as reliable against M. tuberculosis as they are for certain nontuberculous mycobacteria. Due to its lack of antimycobacterial activity, gentamicin is not recommended. Ethionamide has a couple of advantages over aminoglycosides. One is that it can be administered orally. The second is that it penetrates into the CNS better than aminoglycosides and ethambutol. Therefore, ethionamide is frequently used as the fourth drug in tuberculous meningitis. After two months, the PZA and ethionamide (or aminoglycoside) are discontinued, and the INH and rifampin are continued for a total of nine to 12 months.

Although children tolerate the potential toxic effects better than adults, all antituberculous drugs have varying toxicities that may need monitoring. Depending on the drugs being used, these toxicities may include hepatic, neurologic/optic, renal, gastrointestinal injury and hypersensitivity reactions. The specific drugs and their adverse effects are discussed in the Red Book.

Corticosteroids

Another aspect of therapy is the use of corticosteroids. CNS tuberculosis is one of the indications for their use. This obviously modulates the associated inflammation, thereby reducing some of the adverse effects associated with it. Mortality is also thought to be less in steroid-treated patients when compared with those not given steroids. As pointed out in the Red Book, most experts recommend using 1-2 mg/kg/day of prednisone, to a maximum of 60 mg per day for four to six weeks, then tapering the dose over a couple of weeks, while making sure that the patient is taking the prescribed antituberculous drugs, as untreated TB and steroids would obviously be a bad idea.

The child presented is still being treated and is doing well clinically. Her SIADH improved with fluid restriction but did not resolve until treatment for her TB was begun. Of course, SIADH can occur with virtually any pulmonary disease or meningitis. It was routinely seen in children with Haemophilus influenzae type b meningitis in the bad old days. Like treating many conditions, targeting the underlying cause is necessary before SIADH can be resolved.

Skin testing

Lastly, this is probably a good time to review TB skin testing. The indications for and interpretation of TSTs are outlined in the Red Book. The use of the multipronged test is no longer recommended due to its lack of sensitivity and specificity; only the intradermal test with 5 tuberculin units of PPD is recommended. Also, routine testing of all schoolchildren is no longer recommended, although convincing local school districts can be challenging. One of the indications for testing is children immigrating from endemic countries, such as Africa. The child presented may have been diagnosed a bit later if not for the routine testing by the health department because of her recent travel status from Africa. The test should be placed by a provider experienced in administering this intradermal test. It should be done after an alcohol prep with a 27-gauge needle with a 1.0 mL (TB) syringe on the volar surface of the right arm as shown in Figures 13, 14 and 15. When done properly, there should be a visible wheal raised at the injection site. If this is not seen, then the injection is too deep and will render the test unreliable. The patient should have the test read between 48 and 72 hours later by medical personnel experienced in the measurement and interpretation of the test. At 24 hours, there is not likely to be much of a response (Figure 16), as compared with the reaction seen later (Figures 17 and 18). Evaluating a test involves feeling for induration at the site. Erythema does not count for interpretation, only induration. To measure the induration, most people use the ballpoint pen technique, whereby you draw a line from a point beyond the reaction in a direction toward the reaction as shown in Figure 19. When resistance is met, the edge of the induration is defined. This is repeated in all four quadrants. Then the diameter of the area of induration is measured in millimeters (Figure 20). As stated above, interpretation of the results can be found in the Red Book, but again, the measurement and interpretation should NEVER be left up to the parents of the child as this has historically led to many mistakes. As you can see, my TST measures about 18 mm. Like many of you, I converted my TST when I was a medical student. While I don’t recommend it, every few years I volunteer to have the test placed for teaching purposes. That’s how uncommon TB is in our neck of the woods. However, if you live in an area where immigrants from endemic areas are migrating, like the area of Maine where Dr. Hale lives, you will become an expert in short order.

Columnist comments

I think to be an expert on a subject, one needs to not only know the written knowledge of it, but also have significant firsthand experience with it. Given this definition, I do not consider myself an expert on the management of TB. We simply don’t see enough pediatric TB in Central Texas to have the significant experience needed. However, I know who the experts are and how to contact them, and this will be true of all your infectious disease consultants who are in the same situation that I am in. And this is really what you want in a consultant: someone who knows the literature (or at least where to find it) and knows who to talk with in the event of a complication.

The experts whom I look toward for guidance are Jeffrey R. Starke, MD, at Baylor College of Medicine, who has guided the content of the TB chapter in the last several editions of Feigin & Cherry’s “Textbook of Pediatric Infectious Diseases,” and Richard F. Jacobs, MD, at the University of Arkansas, who also teamed up with Dr. Starke to write the chapter on TB in the Long, Pickering and Prober textbook, “Principles and Practice of Pediatric Infectious Diseases.” There are many other “TB experts” around the country with whom your ID consultants will be familiar if needed.

You may have noticed that I referred to the Red Book quite a bit in the above discussion. The complexity and importance of an infectious disease are usually reflected in the amount of space given to the disease in the Red Book. The first Red Book, published in January 1938, was only eight pages, and TB was given one-third of a page, a lot considering that there was no treatment available at that time. In the current, 2003 Red Book, M. tuberculosis is given 19 full pages. HIV surpasses TB by a few pages and hepatitis B falls short by a few pages. No other single entity comes close. While TB has not had the political and cultural/social impact of diseases like smallpox and plague, it has had some historical significance along the way. TB can be traced back thousands of years through work with Egyptian mummies. I would invite you to Google the history of TB to find all you can possibly read on the subject.

Pediatricians in uniform

Lastly, I can’t end this column without my usual appeal to support our uniformed troops and especially the pediatricians, both here and abroad. It is never pointed out how hard those pediatricians left behind have to work when some of their colleagues are deployed. The patients keep coming regardless of the pediatric clinics being short staffed. In fact, they are usually short staffed when they are at “full strength.” Yet they manage to deliver care to Army, Navy and Air Force dependent children that can be compared with some of the best clinics in the world. Additionally, I would also point out that the Public Health Corps Pediatricians (the fourth arm of the uniformed services) also work in austere, short-staffed conditions. They may not be deployable to a combat zone, but they perform a vital service to their patients as well, usually in very remote locations.

That being said, many of the uniformed pediatricians will be converging on San Antonio next month for their annual meeting, The 39th Annual Uniformed Services Pediatric Seminar (USPS). It is co-sponsored by the AAP and the Uniformed Services Section and has grown to be one of the best, if not The Best, general pediatric meetings one can find. It will be four days long, from March 20th through the 23rd. I am honored to be participating with a “visual diagnosis dog and pony show,” but in spite of that, there will be some very worthwhile sessions and workshops. If you are interested in attending, just go to the AAP Web site (www.aap.org), go to the CME page and you will find it. If you have trouble, just let me know and I will give you all the information you need. I hope to see you there. I would like to thank Dr. Dan Hale for his contribution of this very interesting case to this column. — James H. Brien, DO

For more information:

• James H. Brien, DO, Pediatric Infectious Disease, Scott and White’s Children’s Health Center and Associate Professor of Pediatrics, Texas A&M University, College of Medicine, Temple, Texas. E-mail: jhbrien@aol.com