Journal of Clinical and Scientific Research

REVIEW ARTICLE
Year
: 2022  |  Volume : 11  |  Issue : 3  |  Page : 175--180

Opportunistic infections in patients with haematological malignancies in Nigeria


Bassey Ewa Ekeng1, Kingsley Akaba2, Christian Ide3, Rita Oladele4,  
1 Department of Medical Microbiology and Parasitology, University of Calabar Teaching Hospital, Calabar, Nigeria/Medical Mycology Society of Nigeria, Lagos, Nigeria
2 Department of Hematology and Blood Transfusion, University of Calabar Teaching Hospital, Calabar, Nigeria
3 Department of Medical Microbiology and Parasitology, University of Calabar Teaching Hospital, Calabar, Nigeria
4 Department of Medical Microbiology and Parasitology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria/ Medical Mycology Society of Nigeria, Lagos, Nigeria

Correspondence Address:
Bassey Ewa Ekeng
MD, Department of Medical Microbiology and Parasitology, University of Calabar Teaching Hospital, Calabar, Nigeria/Medical Mycology Society of Nigeria, Lagos
Nigeria

Abstract

Haematological malignancies (HM) are common clinical conditions encountered in Nigeria. Patients with haematological cancers are immunocompromised and as such are at risk of invasive fungal infections (IFIs). The objective of this review was to highlight the paucity of data on IFIs in patients with HM in Nigeria and recommendations on the way forward. A literature search for publications from Nigeria on HM including case reports and reviews from 1961 to 2021 yielded 76 publications of which only 9 (11.8%) reported infections in HM. Eight publications documented infection by viruses while only one publication documented bacterial infection. Viruses (73/93, 78.5%) including human cytomegalovirus (n = 19, 20.4%), Hepatitis B virus (n = 15, 16.1%), hepatitis C virus (n = 6, 6.5%) and human T-lymphotropic virus (n = 2, 2.2%) were the commonest causative agents of infections with HIV (n = 31, 33.3%) as the predominant pathogen. Mycobacterium tuberculosis was the only bacterial agent (n = 20, 20.5%). Reports on infections in patients with HM were mostly from the South-South (n = 4), followed by South West (n = 3) and North Central (n = 2). There were no data on IFIs. The limited information on the profile of IFIs in patients with HM in Nigeria may account for the high morbidity and mortality rates associated with HM. Prospective studies should be carried out as a matter of urgency to bridge this knowledge gap.



How to cite this article:
Ekeng BE, Akaba K, Ide C, Oladele R. Opportunistic infections in patients with haematological malignancies in Nigeria.J Clin Sci Res 2022;11:175-180


How to cite this URL:
Ekeng BE, Akaba K, Ide C, Oladele R. Opportunistic infections in patients with haematological malignancies in Nigeria. J Clin Sci Res [serial online] 2022 [cited 2022 Oct 2 ];11:175-180
Available from: https://www.jcsr.co.in/text.asp?2022/11/3/175/347046


Full Text



 Introduction



Haematological malignancies (HM) are a group of malignant clonal disorders that primarily affect the blood and blood-producing tissues. They are broadly classified into myeloid and lymphoid malignancies.[1] HM are commonly associated with infections due to intrinsic immune deficiency, bone marrow suppression and aplasia following chemotherapy.[2] Infections may be localized within organ systems such as the urinary tract, lungs, endocardium, mucosal surfaces, gastrointestinal tracts or invasive spreading through the bloodstream and causing damage to distal organs. Clinical manifestations are also varied and may be systemic or organ specific.[2],[3] Invasive fungal infections (IFIs) are a major cause of morbidity and mortality, in patients with HM particularly in neutropenic patients and in allogeneic haematopoietic cell transplants (HCT) recipients.[4],[5] Commonest fungi causing IFIs in patients with HM are Aspergillus spp. and Candida albicans, however non-C. albicans and a growing number of other organisms including Cryptococcus spp., Mucor spp, Trichosporon spp. and Fusarium spp. are found increasingly.[4],[5]

The incidence and etiologic agents of IFIs however varies across the globe probably due to the differences in the population of patients at risk, use of antifungal prophylaxis and environmental exposure. A retrospective, single-center cohort study from Brazil, showed 94 cases of IFIs among 664 haematologic patients and 316 HCT recipients. The frequency among patients with allogeneic HCT, autologous HCT, acute leukemia and other haematologic malignancies was 8.9%, 1.6%, 17.3% and 6.4%, respectively with Aspergillosis spp. as the leading IFI (53.2%).[5] In another retrospective study from Italy, 538 proven or probable IFIs (4.6%) were found amongst 11,802 patients with haematologic malignancies with over half (346/538) of the cases caused by Aspergillus spp.[6] In more recent studies, higher incidences have been reported in patients with acute myeloid leukemia (AML) receiving induction remission chemotherapy, acute lymphoid leukemia (ALL) patients and in patients with chronic lymphoproliferative diseases receiving ibrutinib.[5] In a multicenter prospective study from Austria and Germany, out of 304 children with HM, 19 had proven/probable IFIs, mostly due to Aspergillus (n = 10) and Candida spp.(n = 5).[7]

Data on HM in Nigeria have been on the spectrum of HM, clinicopathologic findings, challenges in management and treatment outcomes. There is limited data on infections in HM. A retrospective study from Calabar, Southern Nigeria, showed HM prevalence of 10.5% with the patient age range of 16–74 years. Lymphoid malignancies were higher than myeloid (76.81% vs. 23.91%). Chronic lymphocytic leukaemia (CLL) was the most common HM (n = 36, 26.09%) followed by Non-Hodgkin's lymphoma (NHL) (n = 28, 20.29%) while myelodysplastic syndrome (MDS) and Burkitt's lymphoma (BL) 2 (1.45%) each were the least.[8] From Ilorin, southwest Nigeria, a retrospective study showed HM prevalence of 8.1% and 0.2% of all hospital admissions with an age range of 7 months to 80 years. The various HM documented in the study were: ALL (n = 17, 9.4%), AML (n = 23, 12.7%), CLL (n = 33, 18.2%), chronic myeloid leukaemia (CML) (n = 46, 25.4%), NHL (n = 33,18.2%), Hodgkin's lymphoma (HL) (n = 7, 3.9%), BL (n = 2, 1.1%) and multiple myeloma (MM) (n = 20, 11.0%). CML was the commonest HM observed in this study.[9] In a retrospective study from Makurdi, Northcentral Nigeria, the prevalence of HMs among adult patients who had bone marrow cytology was 49.4% of all haematological disorders. The age range of participants was from 16 to 85 years, with a median of 54.0 years. CLL was the most common HM (24/78, 30.8%), followed by CML (19.2%, 15/78). Others were MDS (11.5%, 9/78), ALL (10.3%, 8/78), MM (10.3%, 8/78), AML (7.7%, 6/78), NHL (6.4%, 5/78), Small lymphocytic lymphoma (SLL) 2.6% (2/78) and HL (1.3%, 1/78).[10] Another retrospective report on HM from the North East (Maiduguri) showed HM prevalence of 6.05% and 0.31% of hospital admissions. Among the haematologic malignancies, NHL was the most frequent, constituting 51.3% while others include: HL (26.7%), CML (5.5%), AML (4.2%), MM (4.2%), ALL (3.8%), CLL (3.4%), MDS (0.4%) and Chronic Myelofibrosis 0.4%. Haematologic malignancies were more common in the younger age group and more common in males than females.[11] None of these reviews reported IFIs. Data on the profile of IFIs in HM within a given locality are essential for the effective management of IFIs in this group of patients. Compared to other climes, there is a dearth of data on the epidemiology of IFIs in patients with HM in Nigeria. In addition, Nigeria has since commenced Haematopoietic stem cell transplantation further adding to the at-risk group for IFIs.[12],[13] The essence of this review was to highlight these knowledge gaps and make recommendations on the way forward.

 Search Criteriaa



A systematic literature search was conducted using PubMed, Google Scholar, AJOL, Cochrane Library and grey literature to identify all published papers regarding the topic 'between 1961 and 2021.' The following search terms: 'Malignancies in Nigeria' and/or 'diagnosis' and 'management' of malignancies in Nigeria were used. References in all relevant papers were also reviewed for additional publications ('snow balling') on malignancies in Nigeria that may not have been published in the searched databases. Publications without patients' country of origin were excluded. Publications without abstracts were excluded. Publications with reviews on both HM and other cancers were also excluded. Only publications written in English were included. Data extracted from each case report and/or reviews included: Associated infections (bacterial, viral, parasitic or fungal) in patients with HM and outcomes.

 Results



Our extensive literature search yielded a total of 76 publications on HM. Of the 76, 8 were case reports, while 68 were reviews. Infections in HM were only documented in 9 (12.7%). Of the 9, 3 were from Benin, 2 from Jos, 3 from Lagos and 1 from Ibadan, [Table 1]. Viral infections were predominant (73/93, 78.5%), with HIV infections being the commonest (n = 31, 33.3%) followed by human cytomegalovirus (HCMV) (n = 19, 20.4%), hepatitis B virus (HBV) (n = 15, 16.1%), hepatitis C virus (HCV) (n = 6, 6.5%), and human T-lymphotropic virus (HTLV) (n = 2, 2.2%). Mycobacterium tuberculosis (n = 20) accounted for 20.5% of infections. There were no data on IFIs and parasitic infections in HM in Nigeria, [Figure 1] and [Table 1].{Figure 1}{Table 1}

 Discussion



One thing common to all the studies is that most of the reports were on viruses (HCV, HBV, HCMV, HTLV and HIV) with variation in the few available studies from one geographical region to another. A prevalence of 20% was reported in the north.[13] Similarly, Osikomaiya reported 26.4% in the southwest.[9] Furthermore, another study[14] reported a prevalence of 2% in south-south. Similarly, another study[18] conducted in Benin south-south, reported a prevalence of 3.4%.This may be attributed to the use of cytotoxic drugs which can sometimes activate dormant virus infections such as HBV, HCV and HIV.[16] In addition, HIV causes marked immunosuppression which may predispose to opportunistic infections by oncogenic viruses such as HBV, HCV, Epstein–Barr virus, Human herpesvirus 8, HTLV, and parvovirus B19.[22] Furthermore, the effect of repeated blood transfusion requirements in patients with HM in our environment where commercial blood donor is still the order of the day accounts for the high frequency of viral infections. Other viral infections associated with HM are cytomegalovirus, herpes simplex virus, varicella-zoster virus, respiratory syncytial virus, parainfluenza viruses, influenza viruses, human herpesvirus-6, BK virus, adenovirus, and human metapneumovirus.[23]

M. tuberculosis infection was the only bacterial infection documented from our review with an infection rate of 3.4% (20/581). Diagnosis of TB was based on bacteriological, pathological, and clinical findings.[18] This was slightly higher than an infection rate of 1.78% (53/2984) reported in a retrospective study from Taiwan, probably because the study in Taiwan involved a larger sample size of participants.[24] HM are characterised by impaired immune responses due to altered Th1 cell response caused by the HM itself or by antineoplastic chemotherapy or haematopoietic stem cell transplantation which is often associated with high doses of corticosteroids.[25] This invariably promotes the progression of latent TB infections to active TB disease. Bacterial infections in patients with HM may also be attributed to neutropenia and mucosal ulcerations predisposing to infections by skin colonisers.[3] The lower the absolute neutrophil count, the higher the rate of infection. An absolute neutrophil count of below 500 mm3, is associated with an increased infection rate while counts of between 0 and 100 mm3, are associated with increased incidence of bacteremia and serious infections.[3] Furthermore, bacterial infections may also occur with normal peripheral granulocyte count due to the formation of functionally impaired immature or neoplastic dysfunctional granulocytes.[22] Antineoplastic agents compromise the ability of neutrophils to eliminate intracellular microorganisms by disrupting chemotaxis and phagocytosis.[26] When not quickly and effectively treated, these infections may cause prolonged hospital stay, economic losses, worsened prognosis, serious morbidity and mortalities.

We found no report on IFIs in HM in Nigeria. This was rather alarming, especially when compared with findings from other regions of the world. A prospective study done in Brazil revealed IFIs prevalence rate of 6.2% among 117 patients with HMs including AML, CML, ALL, HL, NHL, MM, aplastic anaemia, MDS and paroxysmal nocturnal haemoglobinuria. The proven diagnosis was defined as positive culture for fungi on BHI medium, identified in 12 (10.2%) patients (Aspergillus spp.(n = 3), Candida spp.(n = 6), Fusarium spp.(n = 2), and Acremonium kiliense (n = 1) while the probable diagnosis was defined as clinical illness consistent with IFI with supporting radiographic image and detection of galactomannan in serum; seen in seven patients (6%). Crude mortality rate was 6%.[4] A 2-year multicenter prospective study involving eight regions in Asia (Hong kong, India, Taiwan, South Korea, Thailand, Vietnam, Singapore and the Philippines) demonstrated a prevalence of 28.2%, 38.3% and 33.5% for possible, probable, and proven IFIs respectively amongst 412 recruited patients with HM. Aspergillus spp.(65.9%) and Candida spp.(26.7%) comprised the major fungal agents causing IFIs. Overall, the 30-day mortality rate was 22.1%. Definition for possible, probable, and proven IFIs was based on the European Organisation for research and treatment of Cancer/IFIs cooperative group and the National Institute of allergy and Infectious Diseases Mycoses Study Group (EORTC-MSG).[27] A prospective study in Italy identified 147 haematological patients with mycoses (72 possible, 35 probable and 40 proven). Proven yeasts diagnosis was detected by blood culture (C. albicans, n = 6; C. krusei, n = 5; C. parapsilosis, n = 4; Candida spp., n = 6; Blastoschizomyces capitatus, n = 1) and by gastroenteric tract biopsy (Histoplasma capsulatum, n = 1). Proven mould diagnosis was obtained by biopsy (Aspergillus flavus, n = 2; Aspergillus fumigatus, n = 2; Aspergillus spp., n = 1; Rizhopus spp, n = 1 and other molds, n = 8), culture of sterile fluid (A. fumigatus, n = 1), culture of nasal swab (A. fumigatus, n = 1), blood culture (Fusarium spp., n = 1; Acremonium spp., n = 1) and culture of bronchoalveolar lavage (A. fumigatus, n = 2; A. flavus, n = 1; A. niger, n = 1; Aspergillus spp., n = 3). Probable mold infection was present in 35 patients detected by galactomannan antigen assay. Majority of the patients had acute myeloid leukaemia (81.6%) while > 90% (133/147) were severely neutropenic (absolute neutrophil count < 0.5 × 109/L).[28] Though not exhaustive, no data were found from our search for IFIs in patients with HM from Africa. The dearth of data on fungal infections in Nigeria may be due to the lack of diagnostic tools in our environment. Some of the diagnostic tests highlighted in the above studies are not routinely done in our tertiary hospitals. In addition, the poor awareness and the low index of suspicion for IFIs by physicians which ultimately affects requests for investigations on IFIs have also contributed to the paucity of data on IFIs.[29],[30]

The emergence of azole resistance is common amongst organisms causing IFIs in HMs. Prompt identification of the fungal pathogen and susceptibility testing is invaluable for the effective management of the patient with HM.[31],[32] The mainstay for prophylaxis and treatment for IFIs is the azoles. Increased azole resistance in A. fumigatus is a significant challenge in effective management of aspergillosis.[31] Azole resistance in A. fumigatus is mainly by exposure to azole fungicides in the environment used for food production, plant protection, and material preservation. Resistance to azoles may also develop secondary to drug pressure after long-term treatments of chronically infected patients.[32] A. fumigatus resistance to azoles is linked to mutation of the cyp51A gene that encodes for lanosterol 14α-demethylase which mediates the synthesis of ergosterol. Mutations in the cyp51A gene alter the structure of 14α-demethylase leading to reduced binding of azoles and generation of resistant phenotypes.[31],[33],[34] Non-cyp51A mechanisms of azole resistance in A. fumigatus have also been reported which includes the development of biofilms and efflux pump activity.[31],[33] The frequency of molds other than Aspergillus spp.(Mucor spp., Fusarium spp., Scedosporium spp.) causing IFIs in patients with HM is increasing and are intrinsically resistant to azoles (Mucor spp.) while some are multidrug-resistant organisms (Fusarium spp., Scedosporium spp.).[31],[32],[33],[34],[35],[36],[37],[38] Candida spp. have also developed azole resistance largely due to point mutations in ERG11 or the overexpression of ERG11 which encodes for 14α-sterol demethylase, an enzyme involved in the biosynthesis ergosterol. Mutation of the ERG11 gene alters the binding site of the enzyme preventing the uptake of azoles.[35],[36],[37],[38] C. krusei is intrinsically resistant to fluconazole. Its mechanism of resistance to azoles is not completely understood.[36],[38] Azole resistance in Candida glabrata may be intrinsic or due to the formation of multidrug pumps following point mutation of genes (CDR1/CDR2 and MDR1) and transcription factors (TAC1 and MDR1) encoding for efflux pumps.[36],[38] Resistance to echinocandins has also been observed in Candida spp including C. albicans, C. glabrata, Candida tropicalis and Candida auris resulting from mutations in the KFS genes.[36],[38] Candida auris is resistant to most antifungals commonly used in the treatment of IFIs. Mechanism of azole resistance in Candida auris include mutation of the ERG11 gene, upregulation of ERG11 and overexpression of effux pumps.[37],[38]

The need for data on IFIs in HM cannot be overemphasised because of the challenge of antifungal resistance, poor availability and accessibility to antifungal agents and lack of diagnostic tools, especially in Africa and Nigeria in particular, which invariably increases the economic burden of HM. A hospital-based retrospective study from Southern Nigeria showed that the total cost of care for 129 patients with premalignant haematological disorders and malignant haematological disorders was N30,041,900.00 ($82,306.58) with an average total cost of care per patient of N232,882.95 ($638.04). Patients with non-Hodgkin lymphoma had the highest mean cost of care per patient (N373,196.30; $1,022.46). The average monthly expenditure per patient was about N70,000 ($190).[1] It is pertinent for physicians to have a high index of suspicion for IFIs in haematological cancer patients, especially when they present with severe neutropenia either before or following chemotherapy or refractory fever after conventional antibiotics.

Going forward, we need to address these knowledge gaps, build capacity and infrastructure, and increase awareness on the part of haematologists managing these at-risk population. We recommend the following.: Epidemiological studies to determine common etiological agents of infections in HM in Nigeria. The data generated will guide in the development of treatment protocol for patients with HMs at risk of IFIs and other infections. Capacity building in the diagnosis and management of in patients with HMs among health-care providers in Nigeria. Provision of the necessary diagnostics and infrastructure.

In conclusion, there is dearth of data on IFIs in patients with HMs in Nigeria despite extensive evidence detailing these groups of patients being at risk of life-threatening IFIs. This highlights a significant knowledge gap and challenges with the capacity and infrastructure needed to make the diagnosis. We have reviewed the literature over a period of six decades and found only 9 studies on infections in HMs despite a significant proportion of these patients in Nigeria receiving immunosuppressive therapy alongside the immunosuppressive disease entities. There is also the challenge of poor availability and accessibility of antifungal agents and the exorbitant cost of managing these group of patients. It is critical that this knowledge gap is urgently addressed to improve clinical outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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