It is always difficult to come up with a list of differential diagnoses. More often than not, medical students (like me) bounce straight to a certain diagnosis and proclaim victory, upon recognising a certain constellation of signs and symptoms. My favourite combination remains: (1) high-grade fever, (2) productive cough, (3) chest pain, all having lasted for a week. Pneumonia, the classical answer comes. However, this attitude, though understandable, also renders us more susceptible to diagnostic inaccuracy. This is not helped by the fact that patients sometimes deliver mistruths. Such mistruths, usually by the form of non-disclosure, can evade our suspicion of more significant diseases. Errors in management delay the administration of proper treatment, leading to less promising clinical outcomes.
Tuberculosis, also known as the ‘Great Masquerader’ [1] due to its various, multi-organ manifestations, is usually not at the top of a differential list. This is especially true in the West, where its prevalence is significantly lower than that of developing nations, such as Indonesia, India and China. 30 high-burden nations account for 87% of worldwide cases. [2] Classical symptoms include fever, chills, night sweat, weight loss (unexplained) and anorexia. [3] Failure of identifying risk factors, such as birth in a high-burden country and immunocompromised status [4], not helped by patient’s non-disclosure, makes it harder to detect in a clinical setting. I present in the following the case of Charlie**, who tested positive for Mycobacterium tuberculosis (the microbe responsible for causing tuberculosis), after being misdiagnosed of community-acquired pneumonia and mechanical back pain.
Miliary Tuberculosis (meaning that the disease is disseminated in multiple organs) Chest X-Ray (PA view) (extracted from Wikipedia)
Charlie was a 64-year old male patient of Thai ancestry. He was reluctant in disclosing his recent travel history and ancestry, as well as immigration history. Previous hospital records indicated only that he was born in Thailand, with a Thai surname. He complained of a 1-month history of acute exacerbation of chronic, lower back pain. It was localised and persistent. The severity of the pain was reported as 9/10 (Visual Analogue Scale), exacerbated by physical exertions and relieved by rest. It alleged to be associated with bilateral lower limb weakness. He also reported nausea and vomiting, chronic productive cough and low-grade fever, all lasting for over a month. The patient had a 20-year history of hypertension and diabetes mellitus, of which the efficacy of control of both was not known. The patient had 5 operations in total, one involving the extensor muscle group of the right arm and one, the left hip. Information regarding the other three operations was unavailable. More importantly, it was unknown where these operations were executed.
Upon physical examination, the patient was feverish and tachypnoeic. There was mild pallor. Chest wall movements were restricted on the right. Percussion notes were dull over the lower right chest (i.e. fourth to sixth intercostal ribs). Basal crepitations could be heard on the right. Spinal movements over the lumbar spine were restricted by pain. Tenderness was present from L2 to L4. Other findings were unremarkable. Blood tests, Chest X-Ray (CXR) and Spinal X-Ray (SXR) were ordered. The patient was slightly anaemic. On the CXR, there were bilateral lung infiltrates, with right tracheal deviation. The SXR showed mild lateral scoliosis of the lumbar spine. The sputum obtained was thick and yellowish. No predominant microbe could be cultured. Urine antigen testing was also unremarkable. Our working diagnosis was atypical pneumonia. Treatment including oral azithromycin, intravenous fluids, and routine monitoring of oxygen saturation, blood gases and urine output, was administered. [5]
Brain CT Scan showing both tuberculoma and hydrocephalus (extracted from Radiopaedia)
Brain MRI (T1) showing multiple tuberculomas (shown as ring-enhancing lesions) scattered across the brain parenchyma. There is posterior fossa involvement (cerebellum and brainstem). This is from a 10-year old female patient. [12]
The patient did not improve. Within the next 24 hours, the patient developed severe, persistent headaches. The patient also had two unwitnessed seizures shortly afterwards. An emergency Brain CT scan was ordered. A ring-enhancing lesion (measured at 5 cm x 5 cm), with associated oedema, was found over the right frontal lobe. Various other small ring-enhancing lesions, of differing sizes, were scattered throughout the brain. Lumbar puncture was also performed. Cerebrospinal fluid analysis revealed a white blood cell count of 450 cells/µL (lymphocyte-predominant). Protein was elevated and glucose was decreased (relative to blood levels). Ziehl-Neelsen Stain was positive. Subsequent PCR for Mycobacterium tuberculosis was also positive. The patient was immediately treated with an intravenous anti-tuberculosis regimen (ethambutol, rifampicin, isoniazid, pyrazinamide), corticosteroids (administered according to local guidelines) and phenytoin.
Acid-fast bacilli (red) cultured in Ziehl-Neelsen Stain (Mycobacterium tuberculosis) (extracted from Wikipedia)
Tuberculosis manifests in various forms. In the central nervous system, it can cause tuberculous meningitis, tuberculomas and tuberculous abscesses. [6] Tuberculosis spondylitis is also expected to have developed in this patient. It is noted that the early radiological signs associated are non-specific and subtle, which could have been easily overlooked. [7] There are two valuable lessons to be gleaned from this case.
Firstly, it is essential that we, as (future) medical professionals, be more assertive when it comes to asking for information relevant to our clinical decision-making. We have erred initially by being too afraid to delve deep into the patient’s biographical details owing to perceived reluctance of disclosure. However, by focusing more on social etiquette and fearing accusations of racial discrimination, we have inadvertently subjected the patient to more pain and suffering. There might be personal reasons behind not disclosing his birthplace, ethnicity, immigration and travel history. They should be accepted in a non-judgmental way. However, as I mentioned, tuberculosis is more prevalent in selected countries. Thailand is classified as a high-burden country by the WHO. [8] As the patient experiences a constellation of both pulmonary and non-pulmonary symptoms, some of which being constitutional, it is advisable to gain more information regarding previous residence and vaccination history. This can be done by stressing to the patient how important this is to making clinical decisions. By being more assertive yet compassionate, diagnostic accuracy can be improved without compromising our professionalism.
Secondly, it is better medical practice to consider a broad range of differential diagnoses. It is recommended not to jump to one or two very likely diagnoses, though tempting by how perfectly the symptoms presented slot into the relevant chapter of the textbook. We have erred in this respect by attributing pulmonary symptoms to atypical pneumonia. The back pain was then considered to be mechanical, owing to an ostensibly normal Spinal X-Ray. It was not until when the patient started having seizures that we realised our mistake. Our initial investigations failed to take into account the possibility of a tuberculosis infection. We also failed to gain more details regarding the patient’s previous surgical admissions. If performed in developing countries, the patient might have acquired HIV during the procedure. [9] This increases the risk of being infected with tuberculosis, where co-infection entails high mortality. [10] Being more open-minded to medical possibilities can help us pick up subtle clues in history-taking and detect ‘masqueraders’ at an earlier stage.
[11] Diagram showing the global epidemiology of tuberculosis.
It is hard being a medical student. Long hours at the hospital and emotional turmoil aside, obscure diagnoses, coupled with patients’ non-disclosure, make matters more complicated. However, all this is normal and we are learning every day. ‘The Great Masquerader’ (Tuberculosis in this case, with syphilis being conferred the title as well) is a clinically significant disease and deserves more of our attention, even if it is not as common in the West. It is always better to be more assertive when asking for material facts and broaden our scope of diagnoses, even though one’s presentation is highly suggestive of a particular pathology. While patient privacy is of utmost importance, being more assertive yet understanding helps us, and ultimately, help the patient.
* This is the case report I've written ages ago about tuberculosis and the active concealment of travel and immigration history by the patient. This can be read together with the earlier article.
** A fake name is used. As the patient has been transferred to another hospital shortly after diagnosis and that it occurred over a year ago, this article is written in a general approach to avoid identification of the relevant party since patient consent cannot be obtained. All identifiable particulars are altered thus.
There are no relevant interests to disclose.
Reference List:
[1] Sievers ML. The Second "Great Imitator"—Tuberculosis. JAMA. 1961;176(9):809-810.
[2] World Health Organisation. Tuberculosis. (Accessed 8 November 2020, at https://www.who.int/news-room/fact-sheets/detail/tuberculosis)
[3] Pitrak D. Diagnosing and Managing Pulmonary Tuberculosis. AMA Journal of Ethics. 2007;9(12):814-818.
[4] American Lung Association. Learn about Tuberculosis. (Accessed 8 November 2020, at https://www.lung.org/lung-health-diseases/lung-disease-lookup/tuberculosis/learn-about-tuberculosis)
[5] File TM Jr, Eckburg PB, Talbot GH, Llorens L, Friedland HD. Macrolide therapy for community-acquired pneumonia due to atypical pathogens: outcome assessment at an early time point. Int J Antimicrob Agents. 2017 Aug;50(2):247-251.
[6] Garg RK. Tuberculosis of the Central Nervous System. Postgraduate Medical Journal 1999;75:133-140.
[7] Harisinghani MG, Mcloud TC, and Shepard JA. Tuberculosis from head to toe. Radiographics. 20 (2): 449-70.
[8] World Health Organisation. Use of high burden country lists for TB by WHO in the post-2015 era. (Accessed on 8 November 2020 at https://www.who.int/tb/publications/global_report/high_tb_burdencountrylists2016-2020.pdf?ua=1)
[9] Goldberg D, Johnston J, Cameron S, Fletcher C, Stewart M, McMenamin J, Codere G, Hutchinson S, Raeside F. Risk of HIV transmission from patients to surgeons in the era of post-exposure prophylaxis. J Hosp Infect. 2000 Feb;44(2):99-105.
[10] Zenner D, Abubakar I, Conti S, et al. Impact of TB on the survival of people living with HIV infection in England, Wales and Northern Ireland. Thorax 2015;70:566-573.
[11] Dye C. Global epidemiology of tuberculosis. Lancet. 2006;367(9514):938-940. doi:10.1016/S0140-6736(06)68384-0.
[12] Farooq MU, Yonker E. Teaching NeuroImages: central nervous system tuberculomas. Neurology. 2009;72(13):e57. doi:10.1212/01.wnl.0000345357.06768.0c.