Mycobacteria

Illustration of the Lazzaretto vecchio, an island of the Venetian lagoon which served as a colony for sufferers of Hansen's disease, as well as a plague hospital in the late Renaissance-early Modern period.

Image from: "Island of Lazzaretto Vecchio Wellcome L0064136.jpg." Wikimedia Commons. Uploaded October 18, 2014. Accessed June 30, 2023. https://commons.wikimedia.org/wiki/File:Island_of_Lazzaretto_Vecchio_Wellcome_L0064136.jpg

1. Under what age and what conditions are children with tuberculosis usually not contagious?

Answer below.

Children under 10, especially with only adenopathy in the chest or small pulmonary lesions (paucibacillary disease) and nonproductive cough are rarely contagious.

American Academy of Pediatrics. Tuberculosis. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 2021 Report of the Committee on Infectious Diseases. Itasca, IL: American Academy of Pediatrics. 2021: 786-814

2. Patients diagnosed with tuberculosis should also undergo baseline testing for other infections. Which other infections should be tested, according to guidelines?

Answer below.

HIV in all cases, and Hepatitis B and C depending upon the circumstances.

Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, Chaisson LH, Chaisson RE, Daley CL, Grzemska M, Higashi JM, Ho CS, Hopewell PC, Keshavjee SA, Lienhardt C, Menzies R, Merrifield C, Narita M, O'Brien R, Peloquin CA, Raftery A, Saukkonen J, Schaaf HS, Sotgiu G, Starke JR, Migliori GB, Vernon A. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016 Oct 1;63(7):e147-e195.

3. What else should be obtained in a baseline evaluation for a newly diagnosed patient with tuberculosis, prior to initiating therapy?

Answer below.

The patient should undergo sputum smears and culture; drug susceptibility testing; AST, ALT, and bilirubin evaluation; platelet counts; testing for HIV; testing for Hepatitis B and C (depending on circumstances); and diabetes screening. Imaging with chest radiography and an ophthalmological exam should also be undertaken.

4. Which vaccine can suppress TST reactivity for 4-6 weeks?

Answer below.

Measles immunization temporarily suppresses tuberculin skin test reactivity. Reportedly the effect of measles vaccination on interferon gamma release assay characteristics are yet to be determined, so the same recommendation applies.

American Academy of Pediatrics. Measles. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 2021 Report of the Committee on Infectious Diseases. Itasca, IL: American Academy of Pediatrics. 2021: 503-519

5. Name a useful surrogate biomarker in the diagnosis of pleural tuberculosis.

Answer below.

Adenosine deaminase.

Fitzgerald DW, Sterling TR, Haas DW. "Mycobacterium tuberculosis," in: Mandell, Dogulas, and Bennett's Principles and Practice of Infectious Diseases. Bennett JE, Dolin R, Blaser MJ, eds. 9th edition. Elsevier; 2020: 2985-3021.

6. A 12-month-old infant presents to your facility after a 3-week history of progressive fever, vomiting, and lethargy. The child had several preceding contacts with primary care providers and emergency care settings due to the history of vomiting, but in each case was sent home with a diagnosis of a viral syndrome or gastroenteritis. Now, the infant is admitted for right-sided hypotonia and concern for stroke. Contrasted magnetic resonance imaging demonstrates the presence of basilar meningitis. Computed tomography of the chest demonstrates the presence of hilar lymphadenopathy. During your history, you find the family has multiple risk factors for tuberculosis, including prior residence in an endemic country, as well as a relative with a history of chronic cough who recently visited their household.

In addition to the rest of the diagnostic workup for other potential etiologies, list the diagnostic tests available to rule tuberculosis in or out. Be thorough and consider the need for phenotypic data (i.e. susceptibilities).

Answer below.

The approach to diagnosis should be multipronged and initiated as rapidly as possible. First, the infant will need to undergo lumbar puncture. CSF cell counts, glucose, protein, and acid-fast stains and cultures will be necessary to help diagnose or exclude CNS tuberculosis, although of course other causes of meningitis must be borne in mind and excluded according to the clinical scenario. In regards to CNS tuberculosis, acid-fast stains and cultures of CSF in individuals with tuberculosis are notoriously insensitive. Rapid molecular methods (NAATs) are available to help confirm the presence of M tuberculosis in CSF, but of course these do not provide necessary phenotypic data for treatment, except for the Xpert MTB/RIF assay, which can quickly identify possible MDR-TB.

Other tests to consider include interferon-gamma release assays (IGRA) and tuberculin skin tests (TST). In a child of this age (under 2 years), the IGRA result is liable to be indeterminate or even false negative, and thus TST would be preferred, although this is increasingly difficult from a logistical perspective in inpatient settings, as many health systems have stopped training clinical staff in its use. Note that either test is liable to confounding results not only from a child's age, but also immunological status, prior Bacille-Calmette-Guerin immunization, and recent measles immunization (in the case of TST).

Recovery of viable mycobacteria on culture will be essential for determining susceptibilities and directing treatment. As mentioned above, CSF acid-fast stains and cultures can be insensitive. The child's disease is likely secondary to primary pulmonary infection, but obtaining sputum specimens in children younger than 2 years is often impossible. The diagnostic specimen of choice for staining and culture in young children in whom cough is absent or nonproductive and sputum cannot be induced is an early-morning gastric aspirates, which should be collected on 3 different mornings on awakening before feeding or ambulation.

Finally, young children almost never represent the index case of tuberculosis in a household. All household members should undergo IGRA or TST testing for tuberculosis, and those with positive results should be evaluated for active disease. Those with active disease may be able to provide sputa for culture and susceptibility testing, which can be reasonably inferred to have the same phenotypic characteristics as the child's infection.

7. Which manifestation of of tuberculous disease are corticosteroids absolutely and always indicated?

Answer below.

CNS disease.

8. Describe the anticipated CSF chemistries, cultures, and molecular diagnostics in an individual with suspected TB meningitis.

Answer below.

The cell count generally ranges from 1-1500 /mm3, classically with a lymphocytic predominance, although up to a quarter of patients may have a polymorphonuclear predominance, especially early in the course. The CSF protein is often elevated and CSF glucose is often low. Acid-fast bacillus staining and cultures are unreliable in terms of sensitivity. Likewise, PCR testing of CSF for confirmation of M tuberculosis is also highly variable and cannot be used to exclude infection.

Fitzgerald DW, Sterling TR, Haas DW. "Mycobacterium tuberculosis," in: Mandell, Dogulas, and Bennett's Principles and Practice of Infectious Diseases. Bennett JE, Dolin R, Blaser MJ, eds. 9th edition. Elsevier; 2020: 2985-3021.

9. How is MDR-TB defined?

Answer below.

Infection or disease caused by a strain resistant to at least isoniazid and rifampin.

10. How is XDR-TB defined?

Answer below.

Infection or disease caused by a strain resistant to at least isoniazid and rifampin, at least 1 flouroquinolone, and at least one of the following parenteral drugs: amikacin, kanamycin, or capreomycin.

11. Which children with active pulmonary or extrapulmonary tuberculosis disease require a lumbar puncture?

Answer below.

ALL INFANTS <12 months.

Variable expert opinion on toddlers 12-23 months

Only those with neurological symptoms greater than 24 months.

12. What is an appropriate rifamycin-class alternative to rifampin in HIV-infected children with tuberculosis?

Answer below.

Rifampin may be contraindicated in individuals receiving antiretroviral therapy. Rifabutin is substituted for rifampin in some circumstances.

13. Resistance to which drug is characteristic of almost all M bovis isolates?

Answer below.

Pyrazinamide.

14. Which mycobacteria is the most common cause of cervical lymphadenitis in children in the United States?

Answer below.

M avium complex.

Strnad LC, Winthrop KL. "Mycobacterium avium complex," in: Mandell, Dogulas, and Bennett's Principles and Practice of Infectious Diseases. Bennett JE, Dolin R, Blaser MJ, eds. 9th edition. Elsevier; 2020: 3035-3048.

15. What reservoirs harbor M avium complex typically?

Answer below.

Soil and water sources, including natural and man-made water sources (e.g. pools and hot tubs)

16. What is the treatment of choice in pediatric mycobacterial lymphadenitis?

Answer below.

Surgical excision. Antimycobacterial treatment with 2-3 drugs including a macrolide is a common strategy in cases where surgical excision is incomplete or impossible due to adjacent anatomical structures, although the optimal duration for such is unclear.

17. What defines "rapidly-growing" mycobacteria?

Answer below.

Mature growth in 7 days or less on media plates.

Brown-Elliott BA, Wallace RJ. "Infections Caused by Nontuberculous Mycobacteria Other Than Mycobacterium avium Complex," in: Mandell, Dogulas, and Bennett's Principles and Practice of Infectious Diseases. Bennett JE, Dolin R, Blaser MJ, eds. 9th edition. Elsevier; 2020: 3049-3058.

18. Name some of the "rapidly-growing" nontuberculous mycobacteria.

Answer below.

There are numerous species. Some of the groups include the M fortuitum group, M chelonae-abscessus group, M mucogenicum group, and the M smegmatis group. There is also a fifth group of early-pigmenting rapidly-growing mycobacteria, which includes such species as M flavescens, M neoaurum, and M vaccae, among others.

19. An 18-year-old young man with cystic fibrosis and bronchiectasis is admitted to your facility with a three-month history of declining pulmonary function tests, low-grade fevers, weight loss, and worsening cough. His imaging on admission demonstrates new reticulonodular and cavitary disease. Respiratory cultures are obtained.

Which mycobacteria are commonly implicated in situations like these?

Answer below.

M abscessus subsp abscessus and M abscessus subsp massiliense are increasingly common isolates in cystic fibrosis patients with NTM pulmonary disease in the United States. Other possibilities include Mycobacterium avium complex and M kansasii. In parts of Canada, the UK, and Europe, M xenopi is also a less common isolate found in NTM pulmonary disease.

20. A 15-year-old presents to your clinic with a violaceous 5 mm nodule on the distal phalanx of his right first finger which is beginning to ulcerate. He reports the nodule developed after he received a puncture wound from the spine of a fish he caught during a recent fishing trip. The wound was initially slight, but over the course of two weeks the nodule appeared. A biopsy is arranged in coordination with dermatology, which demonstrates the presence of granulomatous inflammation. Cultures are pending.

Which infectious agent should be considered in his differential diagnosis?

Answer below.

This presentation is classic for a primary cutaneous M. marinum infection. Patients commonly report the development of a violaceous papule or nodule 2-3 weeks following primary cutaneous inoculation from marine wildlife or cleaning a home aquarium. The lesion may progress to ulceration, or more rarely, sporotrichoid spread up regional lymphatics. Note that in clinical practice other environmental mycobacteria may also be encountered in a situation like this, and ultimately treatment will need to be dictated by cultures and susceptibilities.

21. What culture temperature is necessary for isolation of Mycobacterium marinum?

Answer below.

M. marinum grows best on Lowenstein-Jensen medium at 28-30 degrees Centigrade (C).

Akram SM, Aboobacker S. Mycobacterium marinum Infection. [Updated 2023 Feb 25]. In: StatPearls [Internet]. Treasure Island, FL, : StatPearls Publishing, 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441883/

22. Which bacteria is the only one known to infect Schwann cells?

Answer below.

M leprae, the causative agent of Hansen's disease.

American Academy of Pediatrics. Leprosy. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 2021 Report of the Committee on Infectious Diseases. Itasca, IL: American Academy of Pediatrics. 2021: 472-475

23. How is M leprae infection diagnosed?

Answer below.

Histopathology. There are no surrogate tests, serologic tests, or cultures that can be used in the diagnosis of Hansen's disease. Demonstration of acid-fast bacilli in peripheral nerves is pathognomonic for Hansen's disease.

24. A 12-year-old boy with a history of living with a relative with a diagnosis of Hansen's disease presents to your clinic. They were referred by a primary care provider who was concerned about the presence of a skin lesion that has persisted for several weeks. Which of the following skin findings can be found in patients with Hansen's disease?

A. Hypopigmented anesthetic macules
B. Scaly plaques

C. Painless ulcers

D. All of the above

Answer below.

D. All of the above. Leprosy skin lesions can be quite varied. In particular, a diagnosis of leprosy should be considered in any patient with hypoesthetic or anesthetic skin rash or skin patches who has a history of residence in areas with leprosy.

25. Which hereditary condition should all patients with Hansen's disease be tested for prior to initiation of treatment?

Answer below.

Glucose-6-phosphate dehydrogenase deficiency. Adults with Hansen's disease are typically treated with dapsone, rifampin, and clofazimine. Dapsone can cause hemolytic anemia in individuals both with and without G6PD deficiency.