In this case report, we described a 48-year-old human immunodeficiency virus-negative man with pulmonary tuberculosis (TB) who had an incidental finding of concurrent chronic lymphocytic leukaemia. We highlighted the importance of considering other differential diagnoses when patients present with TB or haematological malignancies. We also discussed the difficulties in diagnosis when both of these conditions co-exist and how this affected treatment and management.
Tuberculosis (TB) is a major health problem worldwide. It is ‘one of the top 10 causes of death and the leading cause from a single infectious agent (above human immunodeficiency virus [HIV] and/or acquired immunodeficiency syndrome [AIDS])’.
Immunocompromised patients, including those with haematological malignancies, are at an increased risk of developing active TB and these patients have an increased mortality risk.
On 26 November 2019, a 48-year-old, HIV-negative man presented to the Primary Health Care Facility in Johannesburg, South Africa, with symptoms suspicious of TB. His sputum was collected and sent for GeneXpert testing. This confirmed a diagnosis of rifampicin-sensitive TB. On 28 November 2019 he was referred to the Clinical HIV Research Unit for screening for an observational study called TB Sequel.
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At the screening visit, the patient complained of a 3 month history of cough, fatigue, night sweats, body weakness, loss of appetite, loss of weight, chest pain, shortness of breath, nausea and vomiting. He also complained of an intermittent fever since February 2019. He had no significant family history of malignancy.
On examination, he was generally wasted but apyrexial and the rest of his vital signs were normal. He had cervical and axillary lymphadenopathy and a hepatomegaly (without splenomegaly). His chest examination revealed scattered lung crackles. He was managed by his Primary Health Care Facility according to the National Tuberculosis Management Guidelines and was thus started on treatment for rifampicin-sensitive TB, rifafour (rifampicin, isoniazid, pyrazinamide and ethambutol), pyridoxine and vitamin BCO on the same day.
He was enrolled onto the TB Sequel study on 02 December 2019 and routine baseline investigations were performed.
Blood results from the patient’s clinic and hospital notes.
| Test: Full blood and differential count | Date and values |
Reference range | |
|---|---|---|---|
| Monday, 02 December 2019 | Wednesday, 11 December 2019 | ||
| White cell count | 150.43 x 109/L | 123.90 x 109/L | 3.92–10.4 x 109/L |
| Haemoglobin | 13.0 g/dL | 12.2 g/dL | 13.4–17.5 g/dL |
| MCV | 80.6 fL | 83.3 fL | 83.1–101.6 fL |
| MCHC | 30.7 g/dL | 30.4 g/dL | 33.0–35.0 g/dL |
| Platelet count | 584 x109/L | 503 x 109/L | 171–388 x 109/L |
| Neutrophils | 7.52 x 109/L | 12.39 x 109/L | 1.60–6.98 x 109/L |
| Lymphocytes | 141.37 x 109/L | 95.96 x 109/L | 1.40–4.20 x 109/L |
| Monocytes | 1.50 x 109/L | 1.21 x 109/L | 0.3–0.8 x 109/L |
| Eosinophils | 0.00 x 109/L | 1.21 x 109/L | 0.00–0.95 x 109/L |
MCV, mean corpuscular volume; MCHC, mean corpuscular haemoglobin concentration.
The patient was admitted to a tertiary public hospital in Johannesburg on 11 December 2019 for further investigation. His full blood count, differential count and peripheral smear upon admission showed a profound absolute lymphocytosis, comprising predominantly small mature forms, with occasional smudge cells and large granular lymphocytes. Approximately 3% of these were larger more primitive cells with features in keeping with prolymphocytes. No increase in blasts was noted. No other secondary causes for eosinophilia and thrombocytosis were discovered and both were regarded as reactive in nature. His lactate dehydrogenase (LDH) from 12 December 2019 was 262 U/L (reference range: 100–190 U/L). His renal function and liver function tests were normal.
A bone marrow aspirate and trephine biopsy was performed on 12 December 2019 and referred to the National Health Laboratory Service for routine analysis. The report described a hypercellular bone marrow with extensive diffuse infiltration by small mature lymphocytes. Fluorescence
These morphological and immunophenotypical findings were in line with a diagnosis of CLL.
A staging computed tomography (CT) scan was performed on 18 December 2019, which showed an extensive bilateral tree-in-bud pattern, and a right-sided pleural effusion, both are suggestive of active pulmonary TB. Signs of pulmonary artery hypertension as well as supraclavicular, mediastinal and intra-abdominal lymphadenopathy were also noted. Furthermore, a thrombus in the inferior vena cava (IVC) was seen, starting from the level of the renal veins and extending distally. Although a hepatomegaly was found on clinical examination, the CT scan confirmed a normal liver and spleen, with no focal lesions. An echocardiogram was performed on 19 December 2019, which was normal.
Based on all of the above results, the patient was classified as stage I under the Rai classification and stage B using the Binet classification of CLL.
The patient was initially anticoagulated and monitored by the tertiary public hospital’s coagulation clinic for the IVC thrombus and subsequently referred to the oncology unit at Charlotte Maxeke Johannesburg Academic Hospital for further management of his CLL. As cure is rare in CLL, treatment is mainly symptomatic and the risk–benefit analysis of available treatments should be considered on a case-by-case basis.
Ethical approval to conduct the study was obtained from the Human Research Ethics Committee (Medical) of the University of the Witwatersrand (Reference number: R14/49, Protocol No: M1911204) on 29 January 2020. Informed consent for publication of this case report was obtained from the patient.
This case report of an HIV-negative man, who was initially diagnosed with TB and then was subsequently diagnosed with a concurrent haematological malignancy, highlights some important factors in the diagnosis and management of both of these conditions.
We will start by discussing the differential diagnoses of an elevated white cell count in the setting of an active infection, like TB. We will then discuss how various haematological malignancies result in immunocompromise, which increases the risk of TB. We will also discuss the difficulties in the diagnosis of both of these diseases because of symptom overlap and atypical presentations. Lastly, we suggest that where economically viable, appropriate workups should be performed to investigate for other diseases.
When faced with a patient who has TB, or another active infection, and a markedly elevated white cell count, it is important to consider a range of causes for leukocytosis. A rare cause of a markedly elevated white cell count is a leukemoid reaction.
An accurate definitive diagnosis of the cause of the elevated white cell count should be made timely. A case series documented three cases of delayed diagnosis of myeloproliferative disorders, which were mistaken as leukemoid reactions in the setting of mycobacterial infection.
Typically, a leukemoid reaction’s leukocytosis predominantly involves neutrophils of a polyclonal nature.
Immunocompromised patients are at an increased risk of developing infections such as TB. They are also at an increased risk of latent TB becoming active TB.
Because of the high prevalence of TB in South Africa, it is often near the top of a differential diagnosis list when treating patients presenting with constitutional symptoms, like those seen in our patient. A retrospective study performed in KwaZulu-Natal found that 18 out of the 21 patients (85.7%), who were found to have lymphoma, had been treated for TB in the preceding year before the diagnosis of lymphoma was made.
It can be very difficult to differentiate between active TB and various haematological malignancies because the symptoms present in both diseases are often very similar. Active TB often presents with some or all of the following symptoms: cough, fever, weight loss, night sweats, haemoptysis, chest pain and fatigue. Some of these symptoms are also common in haematological malignancies, which make an accurate diagnosis difficult. This was demonstrated in a retrospective study performed at a cancer centre in the United States of America, which found that one-third of patients who were referred to the unit for a suspected malignancy between 2006 and 2014 were diagnosed with active TB with no co-morbid cancer.
Another common finding in both diseases and present in our patient is the presence of lymphadenopathy. In the absence of a definitive diagnosis, the cause of lymphadenopathy should be investigated. An article by Antel and Verburgh describes the difficulties in sampling and diagnosing lymphadenopathy in various areas of the body and highlights the mistakes often made by clinicians, leading to misdiagnosis or late diagnosis of malignancies.
Another issue of concern with both these conditions is that immunocompromised patients, including those with haematological malignancies, with active TB often have atypical radiological findings that could confuse the treating clinician.
As mentioned previously, it may be difficult to ascertain which symptoms are caused by a haematological malignancy and which are caused by TB as both of these overlap. South Africa has a high burden of TB and for this reason, patients who present to their local clinic with symptoms suggestive of TB are tested. If TB is found, these patients are treated appropriately. As part of the National Tuberculosis Management Guidelines, baseline blood tests are not routinely performed in these patients.
As described in this study, there is a significant overlap between symptoms present during active TB and constitutional symptoms of haematological malignancies. It is therefore important to investigate thoroughly, follow diagnostic algorithms and use sound clinical judgement when treating these patients. In countries like South Africa, where the incidence of TB is high in the general population, it is important to treat patients with TB appropriately and timely. However, not all symptoms indicate TB. Patients need to be worked up appropriately and, where economically viable, the possible presence of other conditions should be investigated.
The authors thank the TB Sequel Network and the Funding Initiative of the German Federal Ministry of Education and Research (BMBF) for funding the TB Sequel Study (grant number 81204846). They also thank the TB Sequel Study Team for giving them the permission to write up this case report.
The authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article.
V.R.P. was responsible for writing the case report. J.A.B. and I.M.S. contributed to the editing and revising of this case report.
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Data sharing is not applicable to this article as no new data were created or analysed in this study.
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.