ACW Lee, YL Lau, SY Ha, KY Yuen, GCF Chan, RHS Liang, TK Chan, CY Yeung

Abstract

Infections remain one of the major complications of bone marrow transplantation (BMT). Among the first 23 allogeneic paediatric BMT carried out in Queen Mary Hospital from September 1991 to January 1995, there were 68 episodes of infectious complications. These included 19 (28%) pyrexia of unknown origin, 11(16%) clinically documented infections, and 38(56%) microbiologically documented infections. The pathogens identified were of bacterial (n=22, 58%), mycobacterial (n=2, 5%), fungal (n=4, 10%), viral (n=9, 24%) and protozoal (n=1, 3%) in origin, including 21 episodes of bacteraemia. Five children died after BMT of which 4 were directly related to infections (sinopulmonary aspergillosis 2, cytomegalovirus pneumonitis 1, microsporiosis 1). Thus infectious complication is a major cause of morbidity and mortality in children receiving BMT. Thorough investigation for the focus and cause of infections is a pre-requisite for successful management.

Introduction

Bone marrow transplantation (BMT) is a treatment modality for a variety of paediatric malignant and nonmalignant disorders. For malignant diseases like leukaemia or lymphoma, the harvested bone marrow is used as a rescue therapy after high-dose, myelo-ablative chemotherapy or chemoradiotherapy (conditioning treatment). Bone marrow harvested from another individual (allogeneic) or from the patient (autologous) may be used. For non-malignant disorders like thalassaemia, acquired or constitutional aplastic anaemia and congenital immunodeficiencies, the harvested marrow functions as a true "replacement therapy" for the defective haemopoietic stem cells.

Complications are many after BMT (Table I), such as infections, haemorrhage, graft-versus-host disease (GVHD), and acute gastrointestinal toxicities. The frequency and severity of such complications depends on the primary disease, the conditioning treatment, the nature of the graft and the types of prophylactic therapy that the patients receive. These complications tend to initiate and interact with each other. Infections, for instance, often follow the myelosuppressive treatment and may complicate severe mucositis, acute GVHD with or without added immunosuppressive therapy, or blood component replacement therapy.¹

Infectious complications after BMT have been well delineated in adult recipients in which the majority of patients are suffering from haemic malignancies.² Very few reports are available in the literature concerning their occurrence in the paediatric population.³ In paediatric transplants, a significant proportion of recipients suffer from congenital diseases such as thalassaemia who have not been exposed to cytotoxic treatment before BMT. Moreover, the indications of BMT may differ from one centre to another such that direct comparison between different series of patients may not be valid. The following article will summarize the types of transplants and infections encountered in the paediatric BMT programme in Queen Mary Hospital.

Materials and Methods

This is a retrospective study in which the clinical and microbiological records of all children receiving BMT in Queen Mary Hospital between September 1991 and January 1995 were analysed. The patients' demography, their primary diagnoses, the types of transplants, conditioning therapies, and complications encountered after BMT were noted. The follow-up was measured from the date of BMT to the date of death or the end of January, 1995, whichever is earlier.

Fever was defined as a single reading of core temperature of 38.5°C or above, or persistent reading of 38.0°C four hours apart. An infection was defined as any febrile episode not related to transfusion, or any clinical signs and symptoms compatible with a infectious process. A recurrent febrile episode within 72 hours of stopping antibiotic therapy would not be counted as a separate episode unless a different focus of infection or organism was found.

For every suspected infectious episode, blood cultures were taken from the peripheral vein and from each lumen of the Hickman catheter. Other appropriate cultures and imaging were ordered pertaining to the clinical signs. The former included bacteriological, fungal, mycobacterial and Blood cultures were repeated twice weekly until fever subsided.

Infectious episodes were classified as one of the 3 categories: (1) microbiologically documented, if both the clinical focus and infecting organism were identified; (2) clinically documented, if a clinical focus was found without an identifiable organism; or (3) fever of unknown origin (PUO), in the absence of a clinical focus and no organism was isolated, and the clinical course was otherwise compatible with an infection. For gram-positive bacteria, which were part of the normal skin flora such as staphylococcus and bacillus, isolated in blood cultures, they were considered as microbiological documentation only if 2 or more sets of samples were positive in the same episode. Otherwise, such episodes would be counted as PUO in the absence of clinical focus.

Empirical antibiotic therapy included ceftazidime (50mg/kg 8-hourly) and amikacin (7mg/kg 8-hourly) intravenously when the focus of infection was not evident on initial evaluation. Amphotericin B and/or vancomycin were added if signs of infection persisted, or when susceptible organisms were isolated. Acyclovir was used for severe mucosal ulceration or proven herpes simplex virus infection~ Gancyclovir or foscarnet was used for suspected or documented cytomegalovirus infection.

Results

From September 1991 to January 1995, 23 allogeneic BMT were carried out in 22 children. Their mean age was 6.6 (0.5-14.2) years and the male to female ratio was 11:12. Their primary indications were listed in Table II and the types of BMT in Table III. All patients received allogeneic grafts and 1 child with thalassaemia received a second BMT from the same sibling donor. The majority of BMT (70%) were performed for congenital disorders.

Conditioning treatment

Except for an infant with severe combined immunodeficiency, all patients were conditioned with combination chemotherapy. Four children with malignancy also received total body irradiation at a midline dose of 12 Gy. The chemotherapy regimens consisted of busulphan and cyclophosphamide (alone 14, with antithymocyte globulin 3), cyclophosphamide (alone 1, with anti-thymocyte globulin 2), cyclophosphosphamide and etoposide (alone 1, with B-CNU 1).

Antimicrobial prophylaxis

No routine anti-bacterial prophylaxis was used in all children. Nystatin, fluconazole or amphotericin lozenges were used as prophylaxis against fungal infections in all cases. Oral acyclovir against reactivation of herpes simplex virus was used in those who were seropositive (n=22). Gancyclovir prophylaxis was used in children who were seropositive for cytomegalovirus and received a matched unrelated donor transplant (n=3). Prophylactic pyrimethamine and co-trimoxazole were used in a child with relapsed acute myeloid leukaemia who was positive for toxoplasma serologically.

Infections

Sixty-eight episodes of infectious complications were observed. These included PUO (n=19, 28%), clinically documented infections (n=11, 16%) and microbiologically documented infections (n=38, 56%).

The clinically documented infections were mostly of respiratory origin. There were 2 cases of sinusitis, 4 cases of pneumonia and 4 cases of interstitial pneumonitis. There was 1 episode of pen-rectal infection where no organism was found. No mortality was reported among this group of patients, nor in patients with PUO.

Of the microbiologically documented infections, the majority were potentially life-threatening attacks. Twenty-one (55%) were septicaemia and the causative organisms were listed in Table IV. Most mortalities, however, were seen in patients with respiratory or gastrointestinal infections. The non-bacteraemic, microbiologically documented infections were listed in Table V. Overall, the pathogens identified were of bacterial (n=22, 58%), mycobacterial (n=2, 5%), fungal (n=4, 10%), viral (n=9, 24%) and protozoal (n=1, 3%) in origin.

Mortality

Five (21%) patients died. Two (8%) patients died in the early period from sinopulmonary aspergillosis and cytomegalovirus pneumonitis respectively. Three (13%) died in the late phase from sinopulmonary aspergillosis, gastrointestinal microsporiosis and cardiac dysrrhythmia of unknown origin respectively. Thus four out of five (80%) deaths can be attributed to infections in our series.

In addition, all patients who died had acute or chronic GVHD at the time of death with sequential or combination immunosuppressive therapies.

Discussion

Our ability to transplant marrow stem cells across the major histocompatibility complex from one individual to another keeps improving. This is often paralleled by an intensification in conditioning chemoradiotherapy and increasingly sophisticated immunosuppressive regimens which rendered the BMT recipient more immunologically handicapped. Infections emerge as one of the major determinant factors to the success of BMT.

Because of the immunosuppressive therapy and the somewhat programmed immunological recovery after BMT, the pathogenic organisms found after BMT follow a certain pattern.⁴ In brief, the initial myelosuppression (neutropenia) and mucosal insults result in pyogenic infections in the first 3 to 4 weeks. Reactivation of latent herpes simplex virus occurred in 80% of seropositive patients before the era of acyclovir prophylaxis, which tends to delay granulocytic recovery and lead to bacterial infections.⁵ In the ensuing 4 to 8 weeks, the risks of pyogenic infection diminished unless further immunosuppression is needed for acute GVHD.⁶ Latent cytomegalovirus infection may become manifest which culminates into the highly lethal interstitial pneumonitis.⁷

After the first 3 to 6 months, the risk of infection is largely determined by the presence of chronic GVHD.⁸ Chronic GVHD may be limited or extensive. In the latter form, multiple organ involvement and failure of immunological recovery rendered the recipient highly susceptible to infections. The presence of functional hyposplenism further predisposes the patients to infections by encapsulated organisms such as pneumococcus.⁹ Pneumocystis carinii pneumonia is now uncommon with routine cotrimoxazole prophylaxis.

As seen in our series, bacteria remain the commonest cause of infection after BMT. Although anti-bacterial prophylaxis has been practised in some studies,³ its effectiveness has not been proven. The palatability, cost and potential complications should also be taken into consideration. Given the promptness and efficacy of treatment as demonstrated in this study, routine prophylaxis is not justified. The high proportion of septicaemic cases in our series probably reflects the degree of immunosuppression. Some of these organisms are seldom seen in the setting of BMT^10,11 while others may have a predilection to indwelling venous catheter,¹² a device that is almost routine in BMT recipients.

Viruses are the second commonest cause of infection in our series. Although some of these may be trivial and resolve spontaneously, others may be potentially lethal even with specific treatment. Cytomegalovirus (CMV) infection is a major threat in BMT as most people are seropositive (i.e. carrying latent infection) in Hong Kong.¹³ Latent infection may become manifest at 1 to 3 months after transplant and may present as pneumonitis, enteritis and hepatitis.¹⁴ Treatment with gancyclovir may be effective but is often complicated by neutropenia.¹⁴ Foscarnet is an alternative provided the patient's renal function is normal.¹⁵ As established CMV infection is difficult to treat, pre-emptive therapy, usually at a lower dose, can be attempted. Viral studies from endoscopic bronchial lavage and CMV viraemia by means of genomic amplications by polymerase chain reaction has been used to detect the early phase of re-activation.¹⁶ While routine anti-CMV prophylaxis may be too toxic and expensive, such selective approach is justified in view of the grave prognosis of CMV diseases.

Fungi are increasingly common among BMT recipients¹⁸ and have been responsible for two deaths in our series. Another infant almost died of Acremonium falciforme gastroenteritis which has been previously reported.¹⁹ Unfortunately, prophylaxis is often not efficacious and treatment of established infection is often complicated by adverse factors such as continuous immunosuppressive therapy (notably steroids), neutropenia and toxicities of amphotericin B.¹⁸ A high degree of suspicion and vigorous attempt at establishing diagnosis remain the cornerstone in the management of mycosis.

Mycobacterial and protozoal infections are uncommon after BMT. The fatal case of microspora gastroenteritis has never been reported previously. Otherwise, the infection is commonly observed in patients with acquired immunodeficiency syndrome, a condition which parallels the degree of immunosuppression after BMT.

As this series consisted of a large proportion of nonmalignant conditions, especially congenital immunodeficiencies, for BMT, we are not surprised that infection stands out as the chief cause of mortality. Acute and chronic GVHD are important contributing factors as they are present in all fatal cases. Their accompanying respiratory, mucosal and gastrointestinal insufficiency and their treatment with steroids, cyclosporin and antithymocyte globulins are most inviting for sepsis. Further improvement in the outcome of BMT will depend on our ability to manage these complications in a more effective way. The roles of recombinant growth factors in shortening the duration of neutropenia²⁰ and augmenting the leucocyte functions²¹ deserve further investigations.

Acknowledgements

We thank the nurses in the Queen Mary Hospital BMT centre and the technical staff in the BMT laboratory for their expert support.

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