Pediatric Annals

Special Issue Article 

When the Great Masquerader Reveals Itself—Tuberculosis

Brittany Hodgson, MD; Benjamin D. Kornfeld, MD; Bridget M. Wild, MD

Abstract

Pneumonia is a clinical diagnosis often treated empirically and successfully on an outpatient basis. When a patient fails to improve, the clinician is left to revisit the differential of pathogens and reconsider the host. Admission, imaging, and invasive and noninvasive testing are part of the toolkit for the severe or atypical case of pneumonia. For fastidious organisms, achieving a culture-proven diagnosis can be quite difficult. This article discusses the screening and testing for tuberculosis, reviews the utility of computed tomography imaging and bronchoscopy with bronchoalveolar lavage in severe or atypical pneumonia, and highlights the barriers to definitive diagnosis even when the causative microbe is on the differential diagnosis when a patient is admitted. [Pediatr Ann. 2017;46(2):e51–e55.]

Abstract

Pneumonia is a clinical diagnosis often treated empirically and successfully on an outpatient basis. When a patient fails to improve, the clinician is left to revisit the differential of pathogens and reconsider the host. Admission, imaging, and invasive and noninvasive testing are part of the toolkit for the severe or atypical case of pneumonia. For fastidious organisms, achieving a culture-proven diagnosis can be quite difficult. This article discusses the screening and testing for tuberculosis, reviews the utility of computed tomography imaging and bronchoscopy with bronchoalveolar lavage in severe or atypical pneumonia, and highlights the barriers to definitive diagnosis even when the causative microbe is on the differential diagnosis when a patient is admitted. [Pediatr Ann. 2017;46(2):e51–e55.]

This article reviews the epidemiology, natural history, screening, and diagnosis of tuberculosis.

Illustrative Case

A previously healthy, fully vaccinated young adult presented to his pediatrician's office with cough, fever, and fatigue he had been experiencing for 1 week while home from college on summer break. A chest radiograph showed a right upper lobe (RUL) opacity, and he was started on azithromycin (Figure 1). After 5 days of continued high fevers, he returned to the office for reevaluation. A complete blood count in the office demonstrated a white blood cell count of 3,100/mcL, hemoglobin of 9.3 g/dL, and platelet count of 114,000/mcL. He was admitted to the hospital and started on intravenous (IV) ceftriaxone. Repeat chest radiograph demonstrated progression of the RUL opacity with a new right lower lobe opacity. Additional tests on admission included a negative result for rapid HIV-1 and 2 antibodies, normal prothrombin time/partial thromboplastin time and fibrinogen, and a blood culture that continued to show no growth after 48 hours. Due to ongoing high fevers, IV clindamycin was started on hospital day 3, a tuberculin skin test (TST) was placed, and an induced sputum culture was sent to the laboratory for analysis. Two days later, the TST showed 0 mm of induration. In conjunction with an infectious disease consultation, his antimicrobial coverage was modified to levofloxacin monotherapy on hospital day 5. Additionally, blastomyces and histoplasma urine antigens, serum fungitell, and repeat blood cultures were taken; they were all negative. The previously obtained sputum culture returned with mixed respiratory flora. The patient remained febrile despite levofloxacin therapy, and a repeat chest radiograph showed new involvement of the left lower lobe. On hospital day 9, the patient underwent bronchoscopy with bronchoalveolar lavage (BAL). Initial BAL fluid cytopathology was normal, and fluid gram stain, KOH (potassium, oxygen, and hydrogen) preparation, and herpes simplex virus polymerase chain reaction (PCR) were negative. Vancomycin and voriconazole were added to his therapy. On hospital day 12, a chest computed tomography (CT) revealed a 2.7-cm cavitary lesion in the RUL with extensive ground-glass opacities throughout the bilateral lung fields (Figure 2). Simultaneously, the acid-fast smear on the BAL fluid returned positive, which was confirmed by tuberculosis (TB) DNA PCR. The patient was started on four-drug therapy with rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE), and the public health department was contacted. Within 24 to 48 hours of starting RIPE therapy, the patient's symptoms improved and his fever resolved. He was discharged home to complete 9 months of therapy through the public health department. His disease was thought to be a case of reactivated TB possibly acquired during a 2-week trip to India 2 years prior, although no previous TST results were known between the trip and the onset of symptoms. He was born in the United States and had no known TB contacts or foreign visitors. A year from the diagnosis, no close contacts or involved health care providers developed TB infection. The patient continues to do well.


            The presenting chest X-ray with right upper lobe infiltrate.

Figure 1.

The presenting chest X-ray with right upper lobe infiltrate.


            (A) Coronal and (B) axial images from a chest computed tomography demonstrating cavitation and bronchiectasis.

Figure 2.

(A) Coronal and (B) axial images from a chest computed tomography demonstrating cavitation and bronchiectasis.

Discussion

This patient presented with classic reactivation pulmonary TB, which was on the differential diagnosis at the time of his admission; even so, it took 17 days from initial presentation to microbe identification. This humbling experience is not uncommon. Tuberculosis remains a difficult disease to diagnose, and empiric therapy is not without risks of medical and social morbidity. We hope to explore the barriers to affirmative diagnosis even, and especially, when the clinical index of suspicion is moderately high.

Tuberculosis

TB is a disease caused by Mycobacterium tuberculosis complex (a group of acid-fast bacilli) that can have pulmonary and extrapulmonary manifestations. Transmission almost always occurs by inhalation of aerosolized organisms expelled from persons with active pulmonary TB during coughing, sneezing, or phonation.1–3 Less commonly, infection occurs by contact with body fluids from an infected person. People with pulmonary cavitation, sputum samples positive for acid-fast bacilli, and frequent coughing are most contagious, with as many as 30% to 40% of close contacts becoming infected.2 Children younger than age 10 years with the disease are generally not considered contagious as they have smaller numbers of organisms in their secretions and do not cough with enough force to aerosolize the bacilli.3,4

The natural history of illness begins with an incubation period after exposure lasting 1 to 6 months and then progressing to either primary infection or, more commonly, asymptomatic latent TB infection (LTBI).4 Primary infection ordinarily features pulmonary involvement (90%) and presents with fever, coryza, night sweats, and weight loss or failure to thrive. Initial chest roentgenography results include enlarged hilar or carinal lymph nodes or lung infiltrates, whereas chronic or progressing disease demonstrates predilection for the upper lobes.3 Children are less likely to develop cavitation classically seen in adult disease.4 Extrapulmonary disease with or without lung involvement is estimated to occur in up to 33% of cases in the US.1 Whereas people with LTBI are not contagious, they may become so as the lifetime risk of reactivation is 10%; over one-half of these cases occur within 2 years of initial infection.2 Other high-risk periods or states of reactivation include adolescence, severe malnutrition, diseases of immunodeficiency, or medically induced immunodeficiency. In early reactivated TB, chest radiographs show new, localized infiltrates in the same lobe as the old primary complex. However, successive radiographs demonstrate cavitary disease and progression toward bilateral patchy infiltrates if the patient is not treated.3

Over the last several decades, the incidence of TB in the US has declined dramatically. Children and adolescents represent roughly 7% of known cases.5 It is estimated that ≥75% of people younger than age 18 years with TB have parents who were not born in the US or who have lived outside of the US for >2 months.5 Of the remaining cases occurring in American children whose parents were born in the US, the burden falls disproportionately on nonwhite children in low-socioeconomic settings.4

Screening for Tuberculosis

Pediatric health care providers must be able to identify and test for latent TB in at-risk children and young adults. As part of annual well examinations, providers should screen patients using a validated questionnaire to determine the risk of LTBI;6,7 these questions establish whether a patient is the child of an adult at high-risk of TB; was born in a country at high risk for TB; has traveled to an area at high risk for TB; has close contact with someone with known or suspected TB; is a resident of a high-risk congregate setting; is a health-care worker; or is a member of another at-risk population. If a patient screens positive (defined as any answer affirming a specific risk factor), the patient should undergo TB testing.

Successful TB screening programs are an important component of most pediatric medical homes and may be incorporated into preventive health visits. When children and young adults present to their medical homes less than once a year, gaps in the screening program arise and other public health strategies may need to be relied upon to ensure adequate screening of patients who are at-risk, including school-based and college-based screening programs. No sooner than 6 months prior to arrival on campus, all matriculating college students should complete the TB screening questionnaire. Continuing students need only to be rescreened when their activities require it, such as with studying abroad in a country at high risk for TB or volunteering in a health care role.8

Testing for Tuberculosis

Patients with a positive TB screening questionnaire should undergo either a TST or an interferon-gamma release assay (IGRA), which can either be the QuantiFERON-TB Gold (QFT-G, Cellestis Limited, Carnegie, Victoria, Australia) test or the T-SPOT (Oxford Immunotec Limited, Abingdon, United Kingdom). Either test is optimally performed no sooner than 8 to 10 weeks after the period of at-risk exposure has concluded.4,7,8

The current TST is by Mantoux method in which purified protein derivative (PPD) tuberculin solution is injected intradermally. The TST should be read 48 to 72 hours after injection to detect the cell-mediated, delayed-type hypersensitivity reaction causing measurable induration at the injection site.7,8 Correct interpretation of the TST results requires a trained health care professional to note the size of the area of induration at the injection site with most healthy children and young adults requiring >15 mm induration for the test to be considered positive.7,8 The induration cut-off decreases to 10 mm for patients with a risk factor for LTBI and to 5 mm for patients at high-risk of having or developing TB disease.7,8

IGRAs are blood tests that detect interferon-gamma (IFN-gamma) release from a patient's CD4+ T-lymphocytes after stimulation with M. tuberculosis complex antigens. Both commercially available IGRAs are enzyme-linked immunosorbent tests on either whole blood (QuantiFERON-TB Gold In-tube assay) or peripheral blood mononuclear cells (T-SPOT.TB assay). Both tests are considered positive when the INF-gamma response exceeds the test cut-off threshold after subtracting the negative control sample value run at the same time.9 Both the TST and the IGRAs are imperfect TB testing methods. Neither method has a clear advantage regarding test sensitivity, although IGRAs offer greater specificity.

Anergy, or lack of response, to the PPD derivative is a specific disadvantage that can arise in certain circumstances with the TST. Anergy can arise in the setting of active TB infection as well as in patients with other severe infections, inflammatory conditions, and/or malnourishment and in patients with HIV or who take immunosuppressive medication. One additional risk of anergy with the TST is recent receipt of live virus vaccinations, including the routine childhood immunizations measles, mumps, and rubella and varicella.1 TST can be performed on the same day as the live virus vaccination and no sooner than 1 month after live viral vaccination.1 Most patients who will have anergy to the PPD derivative will also be more likely to have a false-negative IGRA.9

The decision to perform a TST versus an IGRA begins with a patient's age; all patients younger than age 5 years, Bacillus Calmette–Guérin (BCG) vaccinated or not, should first undergo a TST. All patients older than age 5 years who have been vaccinated against BCG or who are unlikely to return for a TST reading should first undergo an IGRA. Among patients older than age 5 years who are likely to return for a TST reading, either a TST or IGRA is considered acceptable TB testing. Secondary IGRA may be performed as further supportive evidence of either a positive or negative TST depending on the original clinical suspicion; repeat IGRA is necessary only if the first IGRA was indeterminate.4

If either the TST of IGRA are positive, a patient should undergo medical examination and chest radiography to diagnose either LTBI or active pulmonary TB. Although sputum culture is the gold standard for diagnosis, it can take up to 10 weeks for adequate growth4 and is ultimately positive in fewer than one-half of all pediatric clinical cases.2 Microscopic evaluation by acid-fast staining is quick but often negative even in culture-proven cases.10 There are rapid nucleic acid amplification tests available through reference laboratories that are sensitive and specific for detecting M. tuberculosis and rifampin resistance, but the index of suspicion for TB specifically would have to be high enough to justify sending it prior to any other positive testing.

Upping the diagnostic ante: the toolkit for diagnosis when pneumonia is more than community-acquired pneumonia. Knowing that a TST, IGRA, and sputum acid-fast stain can all be negative in cases of TB, it is no surprise to learn that one study conducted in New York revealed a median delay of 15 days from presentation to health care to initiation of therapy for all comers.11 In the illustrative case, the patient was initially treated for presumptive community-acquired pneumonia (CAP), and it was his failure to improve regardless of antimicrobial coverage that forced us to broaden the differential sequentially and move forward with further testing. The Infectious Disease Society of America has guidelines to aid in the decision to pursue more invasive or higher risk evaluations in any patient with pneumonia who fails to improve on empiric therapy for CAP. In both adults and children, worsening of symptoms or failure to defervesce 48 to 72 hours after starting antimicrobial therapy warrants re-imaging for progression of disease and broadening of coverage.12,13 However, up to 25% of adults can take 6 days to respond to appropriate therapy, and prior to any further testing it is recommended that a repeat history be obtained with careful attention to specific risk factors for atypical microbes.12 Although chest CT, thoracentesis, and BAL comprise the toolkit for pursuing definitive diagnosis in nonresponders, there is not strong evidence or language about how soon to commit or which to do first.

CT is the modality of choice for evaluating lung parenchyma. In adults with nonresponding pneumonia, a chest CT is recommended prior to any procedures to help characterize the process and plan for biopsy/lavage.14 As children are more sensitive to ionizing radiation, CT should be reserved for when ultrasound and roentgenography are not able to provide sufficient detail or direct therapeutic intervention. Specifically, chest CT without IV contrast can characterize cavitations, abscesses, congenital malformations, and masses as reasons for treatment failure in cases of pneumonia.

Whereas chest CT offers greater clarity when an anatomic diagnosis must be rendered, bronchoscopy with BAL (or thoracentesis in cases where an effusion is present) can provide certainty regarding the causative organism. Prior to bronchoscopy, it is appropriate to study induced sputum samples. Although young children are less able to produce sputum, children older than age 5 years and adolescents are frequently able to comply.4 Tuberculosis can be diagnosed by sputum staining and eventually culture of affected adults and children, negating the need for bronchoscopy. For the nonresponding case of pneumonia with negative or uninterpretable sputum studies, BAL is preferred over percutaneous parenchyma aspiration and open lung biopsy. In one prospective study of children with CAP, tandem sputum and BAL cultures were positive in 37.5% and 73.8%, respectively.13 Although bronchoscopy with BAL is indicated in the testing of many pulmonary diseases, its utility specifically for infectious diagnostic purposes in adults with pneumonia is less well studied.

Conclusion

Early in medical education we learn to keep TB on the differential as a disease that can present with an expected or unexpected phenotype. Even when the index of suspicion is higher than usual, it can take weeks to secure the diagnosis, leading to more exposures and more morbidity. This illustrative case proceeded typically for testing of nonresponding pneumonia, yet it took 17 days to secure the diagnosis. With the benefit of hindsight, there may have been the opportunity to arrive at TB sooner had multiple induced sputum samples been collected and stained for acid-fast bacilli. However, even with multiple infectious disease and pulmonary specialists consulting, we were ultimately surprised by the BAL stains and DNA PCR. It was not until a definitive diagnosis was made that the patient and his family recalled his travel history to India 2 years prior, despite thorough questioning up to that point.

Lobar pneumonia is a clinical diagnosis. When sequential broadening of empiric coverage fails to produce clinical improvement, it is time to revisit the differential of causative microbes and “up” the diagnostic ante. Electing for CT verses BAL or thoracentesis is not as simple as weighing risks of radiation verses anesthesia or sedation. If more of the lung appears to be affected, it is reasonable to consider that microbiological or cellular diagnosis is imperative to selecting appropriate therapy. When disease progresses locally, imaging may be helpful to elucidate disease patterns or underlying anatomy predisposing to disease sequestration. Conversely, depending on the history and the host, a foreign body could cause recurrent or poorly responsive localized disease. As in this illustrative case, challenging diseases may require both procedures and imaging to reach parsimony.

TB is not endemic to the US, but with the country's diverse and mobile population, the disease is difficult to eradicate. Universal screening for TB risk factors in the pediatrician's office remains key in identifying those with latent TB infection, and testing appropriately with either a TST or IGRA with any new possible exposures is imperative.

References

  1. Centers for Disease Control and Prevention. Core curriculum on TB: what the clinician should know. https://www.cdc.gov/tb/education/corecurr/pdf/corecurr_all.pdf. Accessed January 20, 2017.
  2. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Controlling Tuberculosis in the United States. Am J Respir Crit Care Med. 2005;172:1169–1227. doi:10.1164/rccm.2508001 [CrossRef]
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  8. American College Health Association. ACHA Guidelines. Tuberculosis screening and targeted testing of college and university of students. https://www.acha.org/documents/resources/guidelines/ACHA_Tuberculosis_Screening_April2014.pdf. Accessed January 20, 2017.
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  12. Mandell LA, Wunderink RG, Anzueto A, et al. , Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–S72. doi:10.1086/511159 [CrossRef]
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  14. American College of Radiology. Acute Respiratory Illness in Immunocompetent Patients. ACR Appropriateness Criteria; 2013. https://acsearch.acr.org/docs/69446/Narrative/. January 26, 2017.
Authors

Brittany Hodgson, MD, is a Pediatric Resident, Comer Children's Hospital, Pritzker School of Medicine, The University of Chicago. Benjamin D. Kornfeld, MD, is a Pediatrician and a Health System Clinician, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University. Bridget M. Wild, MD, is a Pediatric Hospitalist, NorthShore University HealthSystem.

Address correspondence to Bridget M. Wild, MD, Pediatric Hospitalist, NorthShore University HealthSystem, 2650 Ridge Avenue, Evanston, IL 60201; email: bwild@northshore.org.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20170120-01

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