Bacteria

Bacterial infections in neutropenic patients are often caused by the spread of commensal flora to previously sterile sites. Fatal septicaemia can result from Gram-negative bacilli such as Pseudomonas aeruginosa, E. coli, Klebsiella spp. and Enterobacter spp. Gram-positive cocci currently cause the majority of documented bacteraemias. The skin pathogen Staphylococcus epidermidis often colonises indwelling venous catheters. The use of broad-spectrum antibiotics can lead to the emergence of toxin-producing Clostridium difficile in the stools. Methicillin-resistant Staph. aureus (MRSA) and bacteria producing extended-spectrum beta-lactamases (ESBLs) leading to antibiotic resistance are becoming increasingly problematic in hospitals.

Bacterial infection in neutropenic patients may be overt – for instance a chest infection with a productive cough or the presence of infected skin lesions (Fig 43.1). However, bacterial sepsis can equally present with non-specific malaise and a pyrexia. In the latter case extensive cultures including blood, nose, throat, stool and urine are indicated.

Fungi

The incidence of invasive fungal infections is increasing and they are a major cause of morbidity and mortality in patients with haematological malignancy.

The most widespread fungal pathogen is Candida. Oral and colonic carriage of the organism is common in healthy people. Invasive Candida infection is most likely in neutropenic patients with indwelling catheters and severe mucositis. Disseminated candidiasis usually presents with a persistent fever and no diagnostic clinical features. Possible organ involvement includes the kidney, lung, heart and liver. Cutaneous emboli may lead to a nodular skin eruption while exudative retinal lesions can be seen through the ophthalmoscope. Candida spp. are grown from blood cultures in only 20% of patients with invasive candidiasis. The addition of candida PCR significantly improves detection rates.

Aspergillus species, particularly Aspergillus fumigatus, are potentially deadly fungal pathogens. Infection is usually via the inhalation of airborne spores and is mainly pulmonary. A chest X-ray may show pneumonia and cavitation (Fig 43.2) but it is an insensitive diagnostic method. Other infected sites can include the paranasal sinuses, skin, central nervous system and eye. Even in disseminated disease, blood and sputum cultures are rarely positive. Thirty per cent of cases of invasive aspergillosis remain undiagnosed and untreated at death. Strategies for earlier diagnosis include regular galactomannan antigen testing, aspergillus PCR, and CT scanning of the chest.

Pneumocystis jiroveci (previously Pneumocystis carinii) is a fungus which causes a potentially fatal bilateral pneumonia in patients with depressed cell-mediated immunity. In haematological practice it mostly affects patients receiving intensive chemotherapy regimens or stem cell transplantation and patients infected with the HIV virus. Bronchoalveolar lavage is useful in diagnosis.

Viruses

Most viral infection in immunosuppressed patients is caused by reactivation of latent organisms. Patients with deficient cell-mediated immunity (e.g. acute lymphoblastic leukaemia (ALL), stem cell transplantation, chronic lymphocytic leukaemia) are particularly susceptible. Important pathogens include herpes simplex, varicella zoster and cytomegalovirus (CMV). Clinical manifestations range from relatively trivial mouth ulcers attributable to herpes simplex through herpes zoster (shingles) (Fig 43.3) with the risk of dissemination to the potentially fatal CMV pneumonitis which complicates allogeneic stem cell transplantation. Measles can be a fatal illness in children with ALL. There may be no specific diagnostic features of viral infection and it must be considered as a possible cause of a febrile illness in the immunosuppressed patient. PCR-based diagnosis may allow earlier therapy of CMV infection after allogeneic stem cell transplantation.

Neutropenia

General measures include the isolation of the patient, laminar airflow rooms, strict hygiene and avoidance of possible contaminants (e.g. uncooked food). Simple precautions such as hand washing by staff are crucial in reducing infection rates.

Antimicrobial prophylaxis may reduce the incidence of infection but there are well-defined adverse effects. For instance, quinolone antibiotic prophylaxis reduces the number of bacterial infections in patients with chemotherapy and transplant-induced neutropenia but this must be balanced against the side-effects of the drug and the potential emergence and dissemination of antimicrobial-resistant organisms. Increased use of antimicrobial agents increases the vulnerability of patients to nosocomial infections (e.g. Clostridium difficile) and community-acquired infections. Prophylaxis also complicates the treatment of a subsequent episode of febrile neutropenia. It appears that the best way to exploit the benefits of prophylaxis is to restrict its use to patients at highest risk such as those with a previous history of neutropenic fever. Similar considerations apply to the use of prophylaxis against fungal infections.

Depressed cell-mediated immunity and hypogammaglobulinaemia

Impaired cell-mediated immunity leads to an increased risk of Pneumocystis jiroveci (carinii) pneumonia and viral infections. Standard prophylaxis against Pneumocystis is oral co-trimoxazole or nebulised pentamidine where this is not tolerated. Aciclovir is effective in reducing the incidence of viral infections. The more toxic drug ganciclovir can be used after stem cell transplantation to give additional protection against CMV. Patients with low-grade lymphoproliferative disorders and myeloma can have significant hypogammaglobulinaemia and suffer recurrent infection. Regular infusions of immunoglobulin may be helpful in these cases.

Post-splenectomy

See page 10.

The pyrexial neutropenic patient

A common clinical problem in haematology is the management of the patient with neutropenia who becomes unwell and/or develops a pyrexia. A subgroup of very carefully defined ‘low-risk’ patients may require only oral broad-spectrum antibiotics but high-risk patients can rapidly succumb to bacterial infection and need prompt inpatient empirical treatment with broad-spectrum intravenous antibiotics even before the infectious pathogen is identified. Blood and other cultures are taken prior to starting antibiotics and a chest X-ray is helpful: investigations, however, should not substantially delay treatment. A microbiological diagnosis is made in only half of these cases.

The empirical antibiotic regimens are designed to provide protection against commonly implicated organisms, particularly those causing life-threatening infection (e.g. Pseudomonas). Regimens are constantly changing – the major groups of drugs are summarised in Table 43.2.

Monotherapy (e.g. meropenem) may be used but in patients at highest risk a combination (e.g. piperacillin/tazobactam and gentamicin) is usually preferred.

Persistent pyrexia or clinical deterioration on first-line antibiotics is a difficult management problem. Often the infectious agent is unknown. The usual approach is to continue investigations while making a change in the antibiotic regimen. A lack of response prompts consideration of empirical antifungal treatment. To limit drug exposure, entirely empirical therapy can be replaced by a ‘pre-emptive’ strategy where only patients with ‘probable’ fungal infection (e.g. suggested by CT of chest) are treated with antifungal agents. Growth factors (e.g. G-CSF) may be given to shorten the period of neutropenia.

Treatment of specific infections

Liposomal amphotericin B has generally been the drug of choice for treatment of established Aspergillus infection and in the empirical antifungal role outlined above, but voriconazole and caspofungin are reasonable alternatives. Azoles, particularly fluconazole, are commonly used in the treatment of Candida infection. Herpes simplex and varicella zoster infections are best treated with aciclovir. Ganciclovir or foscarnet is used for CMV infection after allogeneic stem cell transplantation. Pneumocystis jiroveci (carinii) pneumonia is effectively treated by either high-dose co-trimoxazole or pentamidine.