Infectious Disease

Tuberculous Pleural Effusion

CASE

A 7 year-old girl presents to a hospital in Lilongwe, Malawi with worsening tactile fevers, shortness of breath, and productive cough over the past week. Her mother reports subjective weight loss, but denies night sweats, hemoptysis, or a significant respiratory history.

The patient’s vital signs were significant for a temperature of 100.6 F, pulse of 69, blood pressure of 107/72, tachypnea to 33, and hypoxia to 87% on room air. Her physical exam was notable for diminished breath sounds throughout the right side. An x-ray was performed revealing a large right-sided pleural effusion (Figure 1). A bedside ultrasound was then performed, showing a loculated pleural effusion (Figure 2). The patient underwent a therapeutic and diagnostic thoracentesis, returning straw colored fluid. In addition to standard pleural fluid studies, the patient’s fluid was also sent for Xpert MTB/RIF nucleic acid amplification test given the high prevalence of tuberculosis in the region, eventually returning a confirmatory diagnosis of Mycobacterium tuberculosis

Figure 1. Chest x-ray of a 7 year-old girl presenting with worsening shortness of breath, productive cough, and subjective fevers, found to have a large right-sided pleural effusion.

Figure 1. Chest x-ray of a 7 year-old girl presenting with worsening shortness of breath, productive cough, and subjective fevers, found to have a large right-sided pleural effusion.

Figure 2. Still image of a point-of-care ultrasound performed on a 7 year-old girl with a large right-sided pleural effusion, showing a loculated pleural effusion.

Figure 2. Still image of a point-of-care ultrasound performed on a 7 year-old girl with a large right-sided pleural effusion, showing a loculated pleural effusion.

 FINAL DIAGNOSIS

Tuberculous pleural effusion

 

CLINICAL PRESENTATION

The classic chest x-ray findings of primary pulmonary tuberculosis (TB) are parenchymal consolidation with or without hilar lymphadenopathy. Tuberculous pleural effusion (also known as tuberculous pleurisy) is the second most common form of extrapulmonary TB (after lymphatic involvement) (Figure 3), and is the most common cause of pleural effusions in TB endemic regions.[1] In children, tuberculous pleural effusion most often occur in the setting of primary TB,[2] whereas in adults they occur most frequently due to reactivation disease.[3] Patients typically present with an acute febrile illness with nonproductive cough and pleuritic chest pain, though dyspnea, night sweats, and weight loss can also occur. Most tuberculous pleural effusions are unilateral and, in contrast to our patient, small to moderate in size.[4] On chest x-ray, pleural disease is often appreciated.[5] Loculation of pleural effusions is not uncommon in tuberculous pleural effusion, and is thought to be due to direct pleural infection and the resulting intense intra-pleural inflammation and organization.[6]

Figure 3. Common sites of extrapulmonary TB.

Figure 3. Common sites of extrapulmonary TB.

 

DIAGNOSIS

 Tuberculous pleural effusion should be suspected in patients with pleural effusion and TB risk factors including history of TB infection, TB exposure, or time spent in TB endemic regions. Unfortunately, definitive diagnosis of tuberculous pleural effusion can be challenging. Tuberculin skin test and interferon-gamma release assays do not distinguish between latent tuberculosis infection and active tuberculosis disease, and thus cannot be used for definitive diagnosis. The gold standard of diagnosis remains demonstration of M. tuberculosis in pleural fluid or pleural biopsy specimen.[4] Presumptive diagnosis can reasonably be made in patients with a known history of pulmonary TB and a pleural effusion without any alternative cause.

In the undifferentiated patient, a workup for pulmonary TB should be initiated including sputum smear and culture for acid-fast bacilli (AFB). Next, a diagnostic thoracentesis can be performed. Pleural fluid from tuberculous pleural effusion is typically an exudative, lymphocyte-predominant pleural effusion, and should be sent for smear and culture for AFB, though cultures are positive in less than 30% of HIV-uninfected patients,[4] and only approximately 50% of HIV-infected patients with CD4 counts less than 100 cells/mm3 (a higher sensitivity due to the greater bacterial burden).[7] Pleural fluid should also be sent for analysis, with typical findings shown in Table 1. 

Laboratory test Typical finding
Color Straw colored(14)
Protein concentration >3.0 g/dL(15)
LDH >500 international units/L(15)
pH <7.4
Glucose 60-100 mg/dL(15)
ADA >40 units/L
Cell count 1,000-6,000 cells/mm^3.(16)
Early neutrophil predominance. After the
first few days, lymphocytes predominate.(15)
Table 1. Pleural fluid findings typical for tuberculous pleural effusion.

 A presumptive diagnosis can be made if there is a lymphocytic-to-neutrophil ratio >0.75 and ADA >40 units/L.[8-10] While nucleic acid amplification (NAA) tests for M. tuberculosis that are FDA-approved for use with sputum have not yet been approved for pleural fluid in the United States, some laboratories use NAA testing of pleural fluid as a validated, "off-label" application. If the patient still remains undifferentiated after this testing and there is concern for the medically complex patient or suspected drug resistance, a pleural biopsy can be pursued by thoracoscopy or closed percutaneous needle biopsy with resulting tissue sample sent for AFB smear and culture as well as histopathology for evaluation of granulomas. Additionally, all patients with suspected tuberculous pleural effusions should be tested for HIV infection.

 

TREATMENT

The mainstay of treatment of tuberculous pleural effusion is antituberculosis therapy, the same as active pulmonary tuberculosis. A typical drug regimen consists of isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by isoniazid and rifampin for an additional 18 weeks. Empiric antituberculous therapy is warranted if a presumptive diagnosis is made as described above, and patients typically defervesce within two weeks and pleural fluid is resorbed within six weeks. However, some patients take up to two months to defervesce with fluid resorption taking up to four months. In areas with high rates of antituberculous drug resistance, organism isolation is more critical as it can guide drug selection. Currently, corticosteroids are not recommended as an adjuvant therapy as there is insufficient evidence for benefit.[11] Therapeutic thoracentesis can be considered in patients with larger pleural effusions or significant dyspnea, as it has been shown to more quickly resolve dyspnea, though there is no effect on long-term outcomes.[12,13]

 

DISPOSITION AND CASE CONCLUSION

Empiric antituberculosis therapy was initiated after thoracentesis, with resulting clinical improvement.  The patient was soon thereafter discharged to complete the remainder of her antituberculosis therapy through a directly observed therapy (DOT) program and was doing well at her follow up visit.

 

TEACHING POINTS

  • Tuberculosis is the most common cause of pleural effusions in endemic regions.

  • The gold standard of diagnosis is demonstration of M. tuberculosis in pleural fluid or pleural biopsy specimen.

  • A presumptive diagnosis can be made if pleural fluid shows a lymphocytic-to-neutrophil ratio >0.75 and ADA >40 units/L.

  • Treatment of tuberculous pleural effusions is the same as for pulmonary tuberculosis.


Faculty Reviewer: Dr. Lauren Allister

 


REFERENCES

  1.  Zhai, K, Lu, Y, Shi, HZ. Tuberculous pleural effusion. J Thorac Dis 2016;8:E486-94.

  2. Merino, JM, Carpintero, I, Alvarez, T, Rodrigo, J, Sanchez, J, Coello, JM. Tuberculous pleural effusion in children. Chest 1999;115:26-30.

  3. Torgersen, J, Dorman, SE, Baruch, N, Hooper, N, Cronin, W. Molecular epidemiology of pleural and other extrapulmonary tuberculosis: a Maryland state review. Clin Infect Dis 2006;42:1375-82.

  4. Gopi, A, Madhavan, SM, Sharma, SK, Sahn, SA. Diagnosis and treatment of tuberculous pleural effusion in 2006. Chest 2007;131:880-9.

  5. Seibert, AF, Haynes, J, Jr., Middleton, R, Bass, JB, Jr. Tuberculous pleural effusion. Twenty-year experience. Chest 1991;99:883-6.

  6. Ko, Y, Kim, C, Chang, B, Lee, SY, Park, SY, Mo, EK, et al. Loculated Tuberculous Pleural Effusion: Easily Identifiable and Clinically Useful Predictor of Positive Mycobacterial Culture from Pleural Fluid. Tuberc Respir Dis (Seoul) 2017;80:35-44.

  7. Gil, V, Cordero, PJ, Greses, JV, Soler, JJ. Pleural tuberculosis in HIV-infected patients. Chest 1995;107:1775-6.

  8. Light, RW. Update on tuberculous pleural effusion. Respirology 2010;15:451-8.

  9. Sahn, SA, Huggins, JT, San Jose, ME, Alvarez-Dobano, JM, Valdes, L. Can tuberculous pleural effusions be diagnosed by pleural fluid analysis alone? Int J Tuberc Lung Dis 2013;17:787-93.

  10. Jimenez Castro, D, Diaz Nuevo, G, Perez-Rodriguez, E, Light, RW. Diagnostic value of adenosine deaminase in nontuberculous lymphocytic pleural effusions. Eur Respir J 2003;21:220-4.

  11. Ryan, H, Yoo, J, Darsini, P. Corticosteroids for tuberculous pleurisy. Cochrane Database Syst Rev 2017;3:CD001876.

  12. Bhuniya, S, Arunabha, DC, Choudhury, S, Saha, I, Roy, TS, Saha, M. Role of therapeutic thoracentesis in tuberculous pleural effusion. Ann Thorac Med 2012;7:215-9.

  13. Lai, YF, Chao, TY, Wang, YH, Lin, AS. Pigtail drainage in the treatment of tuberculous pleural effusions: a randomised study. Thorax 2003;58:149-51.

  14. Levine, H, Metzger, W, Lacera, D, Kay, L. Diagnosis of tuberculous pleurisy by culture of pleural biopsy specimen. Arch Intern Med 1970;126:269-71.

  15. Epstein, DM, Kline, LR, Albelda, SM, Miller, WT. Tuberculous pleural effusions. Chest 1987;91:106-9.

  16. Valdes, L, Alvarez, D, San Jose, E, Penela, P, Valle, JM, Garcia-Pazos, JM, et al. Tuberculous pleurisy: a study of 254 patients. Arch Intern Med 1998;158:2017-21.

Things That Go ‘Mump’ in the Night: What to do with Parotid Swelling

CASE

A healthy graduate student presents to the ER in the middle of the night with facial swelling and voice hoarseness. She states that she has been feeling generally unwell with aches and a sore throat for the past two days. Tonight, she took a throat lozenge shortly before going to bed, but awoke a while later with worsening hoarseness, throat tightness, and facial swelling. She states that the swelling is over her jawline and appears symmetric. She provides her license photo, which shows a dramatic difference in the contour of her mandible.

She is allergic to cats, but denies any recent exposure. She has no other known allergies and multiple prior exposures to this brand of throat lozenge. She denies wheezing, abdominal discomfort, and rash. She is only on birth control. She denies any inhalational drug use. She denies any dental pain or recent dental manipulation.

Her vital signs are within normal limits and she is afebrile. She has no stridor, drooling, or dysphonia, but exam demonstrates marked bilateral parotid/submandibular swelling. The region is not tender nor is it erythematous or warm. Her uvula is midline and without swelling. No lesions are noted in the posterior oropharynx. The tongue is unremarkable. She endorses ongoing throat tightness.

Lab work is obtained. She has a mild leukocytosis to 12.8. EBV and Strep are both negative. Given the extent of swelling and her subjective complaint of throat tightness, you obtain CT imaging (Figure 1).

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Figure 1: CT neck.

Figure 1: CT neck.

The radiologist calls you to discuss the case. He says that she has enlargement of bilateral parotid glands and submandibular glands. He notes extensive subcutaneous edema in the retromandibular tissues and upper neck. Fortunately he says her airway looks patent. He inquires, “What do you think is going on?”

You start to worry that she may have mumps. You’ve never seen mumps, but you know it exists. Time for a quick review…

The Background

  • Mumps is a viral illness that is generally preventable by vaccine.

  • Peak incidence is late winter and early spring.

  • Mumps still occurs in outbreaks in closed environments such as college dormitories, military barracks, and schools, but is rare <1 yo due maternal antibodies.

  • An outbreak is defined as ≥3 cases linked by place and time.

  • Mumps is much more likely to occur in unvaccinated individuals than in vaccinated individuals, but there are rare reports of vaccinated patients developing mumps.

  • Transmission occurs by direct contact, respiratory droplets and fomites.  Viral shedding precedes onset of symptoms.

  • Prolonged incubation period of 12-25 days.

The Presentation

  • There is often a non-specific prodrome of myalgias, headache, fever, and malaise.

  • Salivary gland swelling usually occurs within the first 2-3 days of symptom onset.

  • The hallmark of mumps is parotid swelling. It can be painful and tender, but not always, and can last up to 10 days.

  • The swelling can be unilateral (25% of cases) or bilateral. The swelling can start on one side and then progress to involve both sides.

  • Other salivary glands such as the sublingual glands and submandibular glands can swell, but this only occurs in 10% of cases.

  • Associated complications:

    • Orchitis (typically develops 5-10 days following parotitis with high fevers and severe testicular pain).

    • Meningitis (more common in males. May develop before, during or after parotitis. In some cases, meningitis occurs in the absence of parotitis. Associated with CSF pleocytosis).

    • Other rare complications: encephalitis, pancreatitis, and arthritis.

The Differential

  • Many other viral infections can cause parotid swelling (EBV, HSV, HIV, CMV, coxsackie, etc.).

  • Bacterial parotitis presents as typically firm, tender swelling associated with high fevers and toxic appearance. S.aureus is most often implicated.

  • Salivary gland stone, salivary tumor, sarcoidosis, Sjögren's syndrome.

The Work-up

  • Patient should be placed on droplet precautions.

  • At the time of presentation, two laboratory specimens should be drawn. A serum mumps IgM level and a buccal or oral swab should be sent for RT-PCR. At our institution, these are send-out labs.

  • The IgM level should be sent in a red-top tube.

  • The IgM level is not always accurate if the sample is obtained within the first 5-days of symptom onset. Therefore, if the IgM level returns as normal and the RT-PCR has not resulted (or was never sent), the CDC recommends a second serum sample be sent 5-10 days after symptom onset.

  • It is recommended that the parotid gland be “milked” and the swab be taken from the site of Stensen’s duct (buccal mucosa).

  • The swab used for strep testing can be used for the buccal swab.

  • Buccal swabs should be obtained as soon as possible after symptom onset. It provides the best means for laboratory confirmation, particularly in patients who have been vaccinated.

  • A CBC typically demonstrates leukopenia and a relative lymphocytosis.

  • Often serum amylase will be elevated.

The Treatment

  • No specific treatment.

  • 20-30% of cases are asymptomatic.

  • Supportive care with NSAIDs/Tylenol.

  • If a patient is admitted, they should be placed on droplet precautions until parotid swelling resolves.

  • Individuals treated on an outpatient basis should remain at home and minimize contact with others for five days following symptom onset.

  • Vaccination:

    • Patients who are incompletely immunized and at risk during a mumps outbreak (i.e. college students on a campus with mumps cases) should receive two doses or the MMR vaccine separated by at least 28-days.

    • As of January 2018, the Advisory Committee on Immunization Practices (AICP) made a change regarding the MMR vaccination. In the setting of a mumps outbreak, they now recommend those individuals at risk and who are >2 years out from their last MMR vaccination receive a third dose of the MMR vaccine. This recommendation comes following a large study involving university students. Approximately 5000 students who had previously received 2-MMR vaccinations received a third MMR vaccination during an outbreak. There was a significant reduction in the attack rate in those individuals receiving a third dose compared to those who had only received two doses (6.7 vs 14.5 cases per 1000). The effect was more pronounced in those students that had >2 years elapse since their last MMR vaccination.

  • Reporting:

    • Reporting varies state by state. Rhode Island DOH mandates reporting within four days of Mumps recognition.

    • Mumps is not mandatorily reported to the CDC, but often the CDC will be aware and involved in large outbreaks.

Case Outcome

Patient reported that she had previously been completely vaccinated. At the time of her evaluation, two local universities had reported mumps cases. Her presentation occurred prior to the AICP recommendation. Serum IgM and buccal samples were collected. Patient was clinically stable and comfortable with discharge. She was advised to stay at home for 5-days. Her IgM levels were undetectable and the buccal PCR returned as negative. She most likely had a viral adenitis.


Faculty Reviewer: Dr. Kristina McAteer


References

  1. Albrecht, M. (2018). Mumps. In E.L.Baron (Ed.), UpToDate. Retrieved February 9, 2018 from https://www.uptodate.com/contents/mumps.

  2. Center for Disease Control and Prevention. (2017). Mumps. Retrieved from https://www.cdc.gov/mumps/index.html.