Infections

Bacterial meningitis in hematopoietic stem cell transplant recipients: a population-based prospective study

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Abstract

We performed a nationwide prospective cohort study on the epidemiology and clinical features of community-acquired bacterial meningitis. Patients with a medical history of autologous or allogeneic hematopoietic stem cell transplantation (HSCT) were identified from the cohort performed from March 2006 to October 2014. Fourteen of 1449 episodes (1.0%) of bacterial meningitis occurred in patients with a history of HSCT. The incidence of bacterial meningitis in HSCT recipients was 40.4 per 100 000 patients per year (95% confidence interval (CI) 23.9–62.2), which is 30-fold (95% CI 18–51; P<0.001) higher compared with persons without HSCT. Incidence was higher in allogeneic HSCT compared with autologous HSCT (70.0 vs 15.8 per 100 000 patients per year). Causative organisms were Streptococcus pneumoniae in 11 patients, Neisseria meningitidis in two and Streptococcus mitis in one patient. Mortality was 3 of 14 (21%) and 6 of 11 (55%) survivors had sequelae. Nine of 11 patients (82%) with pneumococcal meningitis were infected with a serotype included in the 23-valent pneumococcal polysaccharide vaccine, of whom four developed meningitis despite vaccination. In conclusion, HSCT recipients have a substantially increased risk compared with the general population of acquiring bacterial meningitis, which is mostly due to S. pneumoniae, and disease is associated with high mortality and morbidity. Vaccination is important to prevent disease although vaccine failures did occur.

Introduction

Bacterial meningitis is a severe infectious disease with high mortality and morbidity rates.1 An immunocompromised state has been associated with an increased risk of bacterial meningitis.2 Hematopoietic stem cell transplantation (HSCT) results in an immunodeficiency through several mechanisms.3, 4 First, underlying hematological malignancies may cause neutropenia or abnormal T- or B-cell function with subsequently impaired cellular or humoral immunity. Second, GvHD, which occurs in ~50% of allogeneic HSCT recipients,5 has been associated with an increased susceptibility to infection. Third, HSCT recipients are often treated with immunosuppressive agents, which further increase susceptibility to bacterial infection. Finally, the transplantation preparatory treatment procedures, for example, chemotherapy and whole-body radiotherapy, lead to an immunocompromised state.

Previous studies showed that Streptococcus pneumoniae is a well-known cause of bacterial infections following HSCT.6, 7 Although the risk of infection after autologous and allogeneic HSCT has been well recognized, few studies have reported on the risk bacterial meningitis following HSCT.8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 The number of allogeneic HSCT has increased in the Netherlands in the past decade from 175 in 2008 to 376 in 2012.26 Furthermore, as survival following HSCT has substantially increased over the years, the number of patients at risk is growing fast. In 2006, there were about 4000 patients over 16 years old alive in the Netherlands with allogeneic or autologous HSCT in their medical history. This number increased to about 5500 patients in 2013 (data provided by European Society for Blood and Marrow Transplantation, Dutch National Registry). Therefore, the recognition of infectious complications is becoming increasingly important.

We studied occurrence, presentation, disease course and prognosis of bacterial meningitis in HSCT recipients identified in our nationwide cohort on bacterial meningitis.

Materials and methods

We identified patients with a medical history of autologous or allogeneic HSCT from our nationwide, prospective cohort study on community-acquired bacterial meningitis, performed from March 2006 to October 2014. Methods of inclusion have been described in detail before.27 Patients with bacterial meningitis over 16 years of age were included. Bacterial meningitis was defined as a positive cerebrospinal fluid (CSF) culture or as the combination of a positive blood culture with a relevant pathogen, or positive PCR or antigen test in CSF, with at least one CSF finding predictive of bacterial meningitis consisting of a CSF leukocyte count >2000 cells/mm3, PMN count >1180 cells/mm3, glucose level <1.9 mmol/L, protein level >2gL or CSF/blood glucose ratio <0.23.28 Patients with a neurosurgical device, neurosurgical operation and patients with neurotrauma within 1 month of the onset of meningitis were excluded. Informed consent was obtained from all participating patients or their legally authorized representatives. Data on patient history, symptoms and signs on admission, laboratory findings, radiologic examination, treatment, and outcome were prospectively collected by means of a case record form. Additional information was collected retrospectively about the underlying disease for which HSCT was performed, on time between transplantation and meningitis, presence and treatment of GvHD, and vaccination status. Meningitis was defined as early onset when the infection occurred <100 days post transplantation, and as late onset when the infection occurred at least 100 days post transplantation.6, 9 All patients underwent neurologic examination at hospital discharge, and outcome was graded using the Glasgow Outcome Scale. A favorable outcome was defined as a score of 5, and an unfavorable outcome was defined as a score of 1–4.

The study was approved by the ethics committee of the Academic Medical Center, Amsterdam.

The study period from January 2007 till January 2014 was used to determine the incidence of bacterial meningitis in the general population and in HSCT recipients. Data on the general population was derived from Statics Netherlands29 and data on number of patients with HSCT were provided by the Dutch National Registry of the European Society for Blood and Marrow Transplantation.

Statistical analyses were performed with the use of SPSS statistical software, version 22 (SPSS Inc, Armonk, NY, USA). For numerical and ordinal data the Mann–Whitney U-test was used. For categorical data the Fisher exact test was used. The 95% confidence interval (95% CI) for the incidence was calculated by using the Poisson regression. All tests were two-tailed, and P<0.05 was considered significant.

Results

A total of 1449 patients with bacterial meningitis were included in the cohort from March 2006 to October 2014. Fourteen patients had HSCT in their past medical history (1.0%) of whom 11 underwent allogeneic and three autologous HSCT.

At the start of the study, 4254 patients (1822 allogeneic and 2432 autologous HSCT recipients) over 16 years old were in the registry, and at the end of follow-up 5421 patients (2623 allogeneic and 2798 autologous HSCT recipients) were in the registry, resulting in a total of 34 668 follow-up years of HSCT recipients, of which 15 726 were in allogeneic HSCT recipients and 18 942 in autologous HSCT recipients. The incidence of bacterial meningitis in the Netherlands in persons over 16-year old without HSCT was 1.34 per 100 000 persons per year (95% CI 1.27–1.42). The incidence of bacterial meningitis in HSCT recipients in the Netherlands was 40.4 per 100 000 patients per year (95% CI 23.9–62.2). The risk of bacterial meningitis was 30-fold (95% CI 18–51; P<0.001) higher for HSCT recipients as compared with persons without HSCT. In allogeneic HSCT recipients the incidence of bacterial meningitis was 70.0 per 100 000 patients per year (95% CI 38.8–126.4) and in autologous HSCT 15.8 per 100 000 patients per year (95% CI 5.1–49.2). The risk was 52-fold (95% CI 29–94, P<0.001) higher for allogeneic HSCT recipients and 12-fold (95% CI 4–36; P<0.001) higher for autologous HSCT recipients as compared to persons without HSCT.

Median interval between transplantation and onset of bacterial meningitis was 4 years (range 4 days–13 years; Table 1). Thirteen of 14 patients had late onset of infection (>100 days since transplantation). One patient had an allogeneic HSCT 4 days before bacterial meningitis. The week before HSCT, he was treated with cyclophosphamide, anti-thymocyte globulin and total body radiation. Three patients had GvHD of whom two were treated with immunosuppressive drugs, consisting of dexamethasone and prednisolone in one case each. The other 11 patients did not receive immunosuppressive medication at time of meningitis.

Table 1 Clinical characteristics of HSCT recipients with bacterial meningitisa

The median age of HSCT recipients at the time of the episode of bacterial meningitis was 58 years (range 25–74 years; Table 1). Classic symptoms and signs of bacterial meningitis were present in about two-thirds of HSCT recipients (Table 1). Focal neurologic deficits were present on admission in four patients of whom three had aphasia and one had hemiparesis due to brain stem infarction. Symptoms and signs at presentation in patients with HSCT were similar to the general population of bacterial meningitis patients (Table 2).

Table 2 Comparison between patients with and without HSCT in their medical historya

A lumbar puncture was performed in all patients. Independent predictors of bacterial meningitis (CSF leukocyte count >2000/mm3, PMN count >1180/μL, glucose level <1.9 mmol/L, protein level >2 g/L, or CSF/blood glucose ratio <0.23)28 were absent in 2 of 14 (14%) patients. HSCT recipients more often had low CSF leukocyte counts as compared to patients without HSCT: 64% of patients had a leukocyte count <1000/mm3 (9 of 14 vs 441 of 1321 (33%), P=0.021) and 29% of patients had a leukocyte count <100/mm3 (4 of 14 vs 136 of 1321 (10%), P=0.049).

Neuroimaging (computed tomography) was performed on admission in 13 of 14 HSCT recipients, and showed abnormalities in five patients. All these five patients had sinus opacification indicative of sinusitis, and two patients had also a hypodense lesion presumed to be infarction. During admission cranial MRI (magnetic resonance imaging) was performed in three patients and showed signs of acute infarction in one patient and mastoid opacification in another patient. In one patient cranial MRI showed no abnormalities.

S. pneumoniae was the causative organism in 11 patients, Neisseria meningitidis in two and Streptococcus mitis in one. Nine patients were treated with a combination of penicillin/amoxicillin and a third generation cephalosporin, two received monotherapy with a third generation cephalosporin, two monotherapy with penicillin and one received amoxicillin/clavulanate and tobramycin. Two patients were treated additionally with acyclovir on the suspicion of viral encephalitis. Thirteen of 14 patients (93%) were treated with adjunctive dexamethasone.

Neurological complications occurred in nine patients of whom three patients had cerebral infarction and one had venous sinus thrombosis complicated by hemorrhagic infarction. Five patients had hearing loss and three developed seizures during admission. Seven of 14 patients (50%) had a favorable outcome and three died (21%). Four of 11 (36%) surviving patients were moderately disabled, two due to motor and sensory deficits because of clinical illness polyneuropathy, one due to cognitive impairment, and one because of severe hearing deficits. Hearing loss was present on discharge in four patients. The mortality rate and rate of unfavorable outcome was similar between patients with and without HSCT.

Vaccination status could be obtained for all patients. All three autologous HSCT recipients had not been vaccinated. Of the 11 allogeneic HSCT recipients, seven were vaccinated against S. pneumoniae (Table 3). One patient was not vaccinated as the episode of bacterial meningitis occurred directly following the transplantation. Three patients were not vaccinated because of active GvHD. Of the 11 patients with pneumococcal meningitis, nine (82%) were infected with a serotype included in one of the pneumococcal vaccines; eight were covered by 23-valent pneumococcal polysaccharide vaccine (PPV-23), three by 7-valent pneumococcal conjugate vaccine (PCV-7) and five by the 13-valent pneumococcal conjugate vaccine (PCV-13) (Table 3). Four patients had S. pneumoniae meningitis due to a vaccine-covered serotype despite vaccination with PPV-23.

Table 3 Vaccinations

Discussion

Our study shows that HSCT recipients are at high risk for acute bacterial meningitis. The identified risk was 30-fold higher for HSCT recipients in general and 52-fold higher for allogeneic HSCT recipients as compared with the general population. This is in line with the higher risk of invasive pneumococcal infection after HSCT reported in literature.6, 7 This increased risk of infection in allogeneic HSCT recipients has been associated with functional hyposplenism due to chronic GvHD and preparatory procedures, decreased IgG2 and pneumococcal antibody production following allogeneic SCT, and impaired opsonizing activity for S. pneumoniae.9 For autologous HSCT recipients, the risk is less pronounced and has been described in those patients treated with whole-body radiotherapy as preparatory procedure resulting in functional hyposplenism.30 Whole-body radiotherapy was not reported in the three autologous HSCT recipients in our cohort. However, HSCT recipients are an uncommon group of patients in the bacterial meningitis cohort (1.0%).

Bacterial meningitis patients with a medical history of HSCT present with similar clinical characteristics as the general bacterial meningitis patient population. However, laboratory parameters of infection in both blood and CSF examinations are less marked compared with non-HSCT patients, and the majority of HSCT patients have a CSF leukocyte count of <1000/ml. Physicians may therefore fail to recognize bacterial meningitis and instead diagnose viral meningitis or encephalitis.

To prevent therapeutic delay, a low threshold should be kept for starting empirical antimicrobial treatment in HSCT recipients with a clinical suspicion of meningitis, but atypical CSF results.

In literature we identified 14 case studies with detailed descriptions of 18 patients.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 Causative organisms were S. pneumoniae in 3 of 18 patients (17%) and Listeria monocytogenes in 7 of 18 patients (39%). Enterococcus faecium was reported 3 of 18 patients (17%) and Staphylococcus aureus, Bacillus cereus, Elizabethkinkia meningoseptica and Stomatococcus mucilaginosus were all reported once.

In contrast, the most common causative organisms for bacterial meningitis in HSCT recipients in our cohort were S. pneumoniae and N. meningitidis. Listeria meningitis was not identified among HSCT patients in our cohort. The high incidence of invasive pneumococcal disease after HSCT has been well recognized by earlier studies. A prospective, population-based surveillance study performed during 10 years including 1238 HSCT recipients found an incidence of 590 and 199 per 100 000 transplanted patients for allogeneic and autologous HSCT, respectively.6 A retrospective case–control study of 1154 allogeneic HSCT recipients identified 26 episodes of invasive pneumococcal disease in 11 years, corresponding to an incidence of 956 per 100 000 transplant years.7 Only one of all these cases of invasive pneumococcal disease involved meningitis. Therefore, incidence differs from the incidence of meningitis following HSCT found in this study.

Most of patients in our cohort were diagnosed with late onset infection, which differs from the interval from transplantation to onset of the episode of bacterial meningitis in the reported cases, in which the median interval was 12 weeks (range 10 days–6 years). Fifty percent of patients (8 of 16) had early onset infections (<100 days since transplantation), of which six occurred within the first month since transplantation. European and Canadian surveys observed invasive pneumococcal infection to occur more frequently in the late post-transplant period (>100 days).6, 9 Isolation and reduced social interaction in the early post-transplantation period has been postulated to protect patients from acquiring infection, whereas persistent deficits in humoral and cellular immunity may increase their risk of illness on exposure to the same strains in the community.6

We found the interval from transplantation to onset of the episode of bacterial meningitis to be up to 13 years. This long-term persistence of an increased risk for infections has been identified in other studies. A nationwide observational study from Taiwan found a 10-year cumulative tuberculosis incidence among HSCT recipients of 3.52%, which was significantly higher than in a matched control cohort.31 A 10-year median follow-up study after allogeneic stem cell transplantation for chronic myeloid leukemia in 102 patients found late pneumococcal infections in six patients (median 32 months, range 10–84) and late infections with Gram-positive cocci in five patients (median 10 months, range: 4–84 months).32 HSCT recipients should be informed about their increased risk of bacterial infections and emphasis should be placed on early recognition of the disease and the lifelong increased risk.

We believe that most of the differences between our cases and those found in literature can be explained by publication bias, as both direct complications and uncommon pathogens are more likely to be reported than infections with common pathogens and late onset infections. Furthermore, late onset infections are more likely to be missed do to loss of follow-up. It may be possible that S. pneumoniae meningitis is mainly found after day 100 whereas other causative organisms cause meningitis earlier after HSCT. Our prospective cohort shows causative organisms to be similar for bacterial meningitis patients with and without a medical history of HSCT. Still, as L. monocytogenes meningitis has been described to occur more frequently in immunocompromised patients, empiric antibiotic treatment for HSCT patients should cover listeria.33

We found that HSCT recipients more often experience neurological sequelae and persisting hearing loss compared with patients without HSCT in their medical history. HSCT recipients with bacterial meningitis were found to have lower CSF leukocyte count, which has been related to an increased risk of intracranial complications in an animal model of pneumococcal meningitis.34

Four patients had S. pneumoniae meningitis with a vaccine-covered serotype despite vaccination with the PPV-23. Vaccine-breakthrough S. pneumoniae infections have been described before, especially with the PPV-23 vaccine. In a retrospective series of 47 HSCT recipients who developed S. pneumonia infections, 11% (5 patients) had vaccine failure.35 Two vaccines against pneumococci are available, the PPV and PCV. PPV has the advantage of covering most of the virulent serotypes of S. pneumoniae, but poor immune response is reported in allogeneic HSCT recipients (19% up to 56% after 12 months).36 PCV has been found to produce better immune response (39% at six months and 91% at 12 months), but covers fewer serotypes.37 A 2009 randomized trial on immunization with pneumococcal conjugate vaccine after allogeneic HSCT showed that additional PPV had a boost effect on the PCV-7 response, allowing 41% of the non-responders to PCV-7 to respond.38 A complementary study showed an additional positive effect on the response rates of PPV-23 itself, if given after a dose of PCV-7.39 Despite these promising results we found two patients to have vaccine failure while vaccinated with both PCV-13 and PPV-23. Good protective antibody responses (>60%) to PCV after autologous HSCT have been found.40 International recommendations for both autologous and allogeneic HSCT consist of a three-dose series of PCV followed by one dose of PPV-23 to broaden the immune response. In patients with GvHD, a fourth dose of PCV should be considered instead of PPV-23. Vaccination should be initiated 3–6 months after transplantation.41

Our study has several limitations. The observational design of the study is sensitive to the introduction of confounding factors, which hinder the evaluation of the risk analysis. HSCT may have been underreported in the cohort which may have led to an underestimation of the risk for bacterial meningitis. Furthermore, no detailed information was obtained about the underlying conditions in the HSCT population in the Netherlands. Specific hematologic disorders, preparatory procedures and the use of immunosuppressive medication may be responsible, at least in part, of the observed difference between both the general population and HSCT recipients and autologous and allogeneic HSCT recipients.

Other limitations of this study were that only patients with culture-proven meningitis were included in our cohort study. Not all patients with suspected bacterial meningitis may undergo a lumbar puncture, for example, patients with coagulopathy due to hematologic disorder or sepsis, or those with space-occupying lesions on cranial imaging. These patients were not included in our cohort. Finally, our literature search identified only case reports, which are prone to publication bias and are expected to be non-representative for the whole population. Nevertheless, our study describes the largest number of consecutive HSCT recipients so far from a prospective nationwide cohort and therefore, our study offers a valuable insight in the characteristics of bacterial meningitis in HSCT recipients.

In conclusion, HSCT recipients have a substantially increased risk compared with the general population of acquiring bacterial meningitis, which is caused by S. pneumoniae in the majority of cases. Signs and symptoms at presentation are similar to the patients without HSCT in their past medical history, although CSF and blood leukocytosis are often less marked. Uniform vaccination should be performed using PCV-7, -10, or -13, followed by PPV-23, although vaccine breakthroughs may still occur. As infections are often late onset, HSCT recipients should be subject to prolonged follow-up and vaccination status should be kept adequate.

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Acknowledgements

Ronnie van der Holt, PhD and Jeannine Refos, EBMT coordinator, Erasmus MC HOVON data center provided the data about the prevalence of HSCT in The Netherlands. Netherlands Organization for Health Research and Development (ZonMw; NWO-Vedi grant 2010.[016.116.358] to DB NWO-Veni grant 2012.[916.76.023] to MB), the Academic Medical Center (AMC Fellowship 2008 to DB), and the European Research Council (ERC Starting Grant 281156 to DB). The Netherlands Reference laboratory for bacterial Meningitis is supported by the National Institute of Public health and the Environmental Protection, Bilthoven.

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Correspondence to D van de Beek.

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van Veen, K., Brouwer, M., van der Ende, A. et al. Bacterial meningitis in hematopoietic stem cell transplant recipients: a population-based prospective study. Bone Marrow Transplant 51, 1490–1495 (2016) doi:10.1038/bmt.2016.181

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