As previously mentioned, infections caused by encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) have been reported as being more frequent and more virulent in patients with impaired humoral immunity/hypogammaglobulinemia. However, recent surveys indicate that both H. influenzae and N. meningitidis are now quite uncommon, even in this setting [5, 6]. This decline is most likely the result of herd immunity due to the availability of effective immunization against these organisms and the practice of administering quinolone prophylaxis in high-risk patients. Infections caused by S. pneumoniae are more common but are also on the decline. A recent review of streptococcal bloodstream infections seen at a comprehensive cancer center over a 12-year span documented that the largest number of cases (45.6 %) was caused by S. pneumoniae. However, there was a 55 % decline in frequency from the beginning of the review (2000) to the end of it (2011) [5]. These infections were more common in patients with solid organ malignancies than in patients with lymphomas and/or other groups with impaired humoral defense mechanisms. A significant decline in penicillin-resistant S. pneumoniae was also documented. Only 4 % of the total pneumococcal bacteremias occurred in an age group in which the 7-valent pneumococcal conjugate vaccine (PCV7) is recommended. The authors hypothesize that the continued vaccination of the pediatric population with PCV7 may be a major method of controlling invasive, antimicrobial-resistant pneumococcal disease in the broad cancer population. Other experts prefer the use of the 13-valent vaccine (PCV-13) for primary vaccination followed by booster vaccination with the 23-valent vaccine (Pneumovax-23) [7].

Nocardiosis is caused by several species of Nocardia, the most common of which are Nocardia asteroides complex, N. brasiliensis, and N. otitidiscaviarum (formerly N. caviae). Nocardiosis is uncommon in immunocompetent persons. Approximately half the number of cases occur in individuals with impaired cell-mediated immunity secondary to an underlying malignancy (most often lymphoma) or its treatment. Nocardiosis occurs less often in patients with impaired humoral immunity or with leukocyte abnormalities. T lymphocytes are essential for a host to mount an adequate immune response to Nocardia infection. Although T lymphocytes can kill Nocardia in vitro, their primary role is to activate macrophages and stimulate a cellular response. Infection usually follows introduction of the organisms into the respiratory tract, although it is also acquired via direct inoculation into the skin.

Data from a relatively large study (43 episodes) of nocardiosis in patients with cancer documented that 64 % of these patients had an underlying hematologic malignancy, with lymphoma being the most common [8]. Lymphocytopenia was present in 54 %, 58 % had received corticosteroids, and 24 % had undergone hematopoietic stem cell transplantation. The most common sites of infection were the lungs (70 %) and soft tissue (16 %). Nocardia asteroides complex was the most common species isolated. Central nervous system (CNS) infection and widespread dissemination were uncommon (2 % each). When CNS disease is present, the differential diagnosis is wide and includes other pathogens such as Cryptococcus neoformans, Toxoplasma gondii, and mycobacteria (predominantly M. tuberculosis) which are common in this setting, as well as the underlying malignancy (predominantly lymphoma) itself. Hence, the need for establishing a specific diagnosis is paramount. Trimethoprim/sulfamethoxazole (standard dosage) remains the backbone of therapy. It is often combined with agents such as the carbapenems, tetracyclines, or aminoglycosides [8, 9]. Prolonged treatment (up to 6–12 months) is usually necessary, despite which the mortality rate is around 60 % [10].

Other bacterial infections that occur more frequently in patients with impaired cellular and/or humoral immunity include salmonellosis, legionellosis, listeriosis, and infections caused by Campylobacter and Capnocytophaga species. Bacteremia is the most common manifestation of salmonellosis, although other manifestations including gastroenteritis, cholangitis, septic arthritis, and meningitis also occur [11–13]. The morbidity and mortality associated with salmonellosis is greater in patients with underlying malignancies than in immunocompetent individuals. Resistance rates to antimicrobial agents commonly used to treat salmonellosis (fluoroquinolones, ceftriaxone) may differ from region to region and appear to be increasing in some parts of the globe, although these organisms generally remain quite susceptible to the carbapenems [12]. Although much less common than salmonellosis, gastroenteritis and bacteremia caused by Campylobacter species does occur more frequently in patients with underlying lymphoid and gastrointestinal malignancies. Most cases involve elderly males. In one recent review of Campylobacter bacteremia, the rate of resistance to fluoroquinolones was 32 %, but all isolates were susceptible to imipenem, and 99 % were susceptible to amoxicillin/clavulanate [14]. There is a strong association between antecedent infection with Campylobacter jejuni and Guillain-Barre syndrome (GBS), with about a quarter of patients who develop GBS giving a history of recent C. jejuni infection [15]. This may lead to the generation of antibodies which cause acute axonal damage and result in acute motor axonal neuropathy [16].

Infections caused by Legionella species (primarily Legionella pneumophila) occur in immunocompromised individuals, including those with malignant lymphomas, as well as in immunocompetent individuals [17]. Often, hospital water systems harbor Legionella species, and most cases of hospital-acquired legionellosis can be traced to such sources [18]. Consequently, monitoring of hospital water systems for the presence of Legionella (and other potential pathogens) is mandatory, and guidelines for how to do this and how to deal with outbreaks where they do occur have been published [19]. However, patients with malignant lymphomas may also acquire legionellosis from household water or whirlpools that have been inactive for a while. Pneumonia is the most common manifestation, and it cannot be distinguished clinically or radiographically from other forms of pneumonia [20]. The detection of urinary antigens and/or culture on special media is usually required to make a specific diagnosis. The fluoroquinolones and macrolides are used most often for treatment which needs to be longer in duration in immunosuppressed individuals than in those who are immunocompetent.

Listeriosis is caused by Listeria monocytogenes, a facultative anaerobic gram-positive bacillus. Although L. monocytogenes can infect immunocompetent individuals, those with abnormalities in cellular immunity are at particular risk. The predominant source of infection is the consumption of raw milk or products (cheese) made from raw milk, although some cases have been associated with pasteurized milk as well [21, 22]. In a recent review of listeriosis, 12 of 34 patients (35 %) had an underlying lymphoid malignancy [23]. Lymphocytopenia was observed in 62 % of patients, and 76 % had received prior corticosteroid therapy. In 11 patients listeriosis complicated hematopoietic stem cell transplantation. Bacteremia (74 %) was the most common presentation followed by meningoencephalitis (21 %). Although the overall response to antimicrobial therapy (most commonly ampicillin and gentamicin) was 79 % only, three of six patients with meningoencephalitis responded.

Capnocytophaga species are facultative anaerobic gram-negative bacilli that are part of the normal human oral flora. In one report of 28 patients with bacteremia caused by Capnocytophaga species, 11(21 %) had an underlying lymphoma, and 11 had CLL [24]. Ninety three percent were neutropenic at the onset of infection, and 50 % had moderate to severe mucositis. Capnocytophaga ochracea was the most common species isolated, and 14 % of these infections were polymicrobial. Fluoroquinolone resistance is not uncommon, but the organisms are generally susceptible to beta-lactam antimicrobial agents (penicillins, cephalosporins, and carbapenems).

Cell-mediated immunity plays an essential role in the control of mycobacterial infections. T cells elaborate cytokines that are capable of activating macrophage antibacterial activities [25]. It is this cell-mediated response that is responsible for controlling primary infection with Mycobacterium tuberculosis. Conditions that compromise cell-mediated immunity allow the infection to spread and cause symptomatic disease [25]. Mycobacterial infection in such patients frequently becomes far advanced before it is suspected and diagnosed.

The association between tuberculosis and Hodgkin’s disease [HD] or hairy cell leukemia has been well described [26–29]. Tuberculosis can precede the diagnosis of HD, occur concomitantly, or develop during treatment for HD. It can also develop after HD therapy has been completed, making it difficult to differentiate it from refractory or relapsed disease. These features were highlighted in a recent retrospective review of 70 pediatric patients with HD [26]. Fourteen of these patients (20 %) had pulmonary tuberculosis. In three, tuberculosis was diagnosed before HD, two had both entities concomitantly, in seven it occurred during treatment, and in two patients it was diagnosed post HD therapy. Cough and fever were the most common symptoms, and diffuse pulmonary infiltrates with or without mediastinal enlargement were the most common radiographic findings. Specific therapy resulted in response in all 14 patients.

Nontuberculous mycobacterial infections are less common than tuberculosis in patients with malignant lymphomas [30–33]. They produce pulmonary infections, lymphadenitis, soft-tissue infections, and disseminated disease [30]. The species isolated most often are M. avium-intracellulare, M. abscessus, M. chelonae, M. fortuitum, M. kansasii, and M. marinum. Prolonged, multiple drug therapy is usually administered for actively progressive infection. A detailed discussion of the diagnostic and therapeutic strategies for mycobacterial infections is beyond the scope of this chapter. However, specific guidelines dealing with these issues are available [34, 35].

Invasive mold infections caused primarily by Aspergillus species, and less frequently by the zygomycetes, Fusarium species, and other filamentous fungi are seen not only in patients with prolonged neutropenia but also in those with impaired cellular immunity and prolonged corticosteroid usage. Pneumonia is the most common manifestation of invasive mold infections although fungemia and dissemination to other organs, particularly the CNS, can occur. The clinical manifestations, radiographic features, and histopathologic finding of infections caused by these fungi are often indistinguishable from each other. The diagnosis and management of these infections has been dealt with in detail elsewhere in this volume.

Pneumocystis pneumonia (PCP) has traditionally been associated with impaired cell-mediated immunity resulting in reactivation of a dormant infection [36]. The clinical presentation is usually subacute. Common clinical features include fever, a nonproductive cough, and progressive dyspnea. Often the presentation is subacute, and consequently a high index of suspicion is necessary in the right setting. Patients at risk for PCP who are not receiving prophylaxis and who develop elevated LDH levels often have smoldering infection and should undergo appropriate diagnostic evaluation. The most common radiographic finding is a diffuse bilateral reticulonodular pulmonary infiltrate although atypical lesions such as granulomatous pulmonary nodules have been described [37]. The diagnosis is usually made by demonstrating the organisms on respiratory specimens (including biopsy tissue) using a number of special stains (methenamine silver, Wright-Giemsa, or immunofluorescent staining). High-dose trimethoprim/sulfamethoxazole (TMP/SMX) is the agent of choice for the treatment of PCP and is also strongly recommended for prophylaxis in high-risk patients.

Rituximab is a chimeric human/murine monoclonal antibody which targets the B-cell-specific antigen CD20. It has been used effectively for the treatment of B-cell lymphoma. In recent years, several reports have documented the increasing frequency of PCP in patients with aggressive B-cell lymphoma being treated with R-CHOP 14 (biweekly rituximab, cyclophosphamide, Adriamycin, and prednisone) but not with R-CHOP 21 (the same regimen given every 3 weeks) [38]. Most of these patients were not severely immunosuppressed with CD4+ T lymphocyte counts being >200/mm³ and immunoglobulin levels being within the normal range. It has been postulated by some investigators that the reason for the increased risk of PCP is the greater intensity of corticosteroid exposure as well as the cumulative corticosteroid dose [38]. Others have suggested that B-cell depletion caused by rituximab may play a role in increasing the risk of PCP [39]. PCP prophylaxis is now strongly recommended in this subset of patients and has been shown to be effective [40].

Cryptococcosis is caused by two sibling species, Cryptococcus neoformans and Cryptococcus gattii. The primary site of infection is the lung which follows the inhalation of cryptococcal spores [41]. Dissemination usually involving the CNS occurs in severe cases. Both species cause infection in immunocompetent and immunosuppressed individuals. Several reports have noted the association between cryptococcosis, lymphoproliferative disorders (especially lymphomas), and impaired cell-mediated immunity [42]. In recent reports chemotherapy regimens which include rituximab have been implicated as a risk factor for cryptococcosis [43–45]. Fever and meningeal symptoms are the most common manifestations of cryptococcal meningitis. Cerebrospinal fluid (CSF) abnormalities include raised CSF opening pressure, lymphocytosis, elevated proteins, and low glucose levels. The diagnosis is made by visualization of the organism in the CSF by India Ink staining and/or its recovery on culture. Cryptococcal antigen is also detected in CSF and serum in most cases. Induction therapy with amphotericin B (or its lipid formulations) plus 5-fluorocytosine, followed by maintenance therapy with fluconazole, is the current standard of care. Detailed guidelines for the management of cryptococcosis have been published [46]. Histoplasmosis is far less common than cryptococcosis in cancer patients with impaired cell-mediated immunity [47]. It can cause pulmonary, CNS, or disseminated infection and should be considered in the differential diagnosis in endemic areas of the world.

Toxoplasmosis is one of the most common parasitic infestations in man. Most cases in immunocompetent individuals are asymptomatic [48]. Disseminated disease which can often be fulminant generally occurs in immunocompromised individuals, with the CNS, lungs, and heart being the most common sites of involvement. Toxoplasmosis has occasionally been described in patients with lymphoproliferative disorders (primarily lymphomas). Even in this setting, disseminated toxoplasmosis usually occurs after allogeneic HSCT has resulted in increased immunosuppression [49–52]. In a review of 2,574 transplant procedures performed at 16 participating centers, the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) found the incidence of toxoplasmosis to be 1.9/1,000 in autologous transplant recipients and 8/1,000 in allogeneic transplant recipients [53]. The group postulated that the relative rarity of toxoplasmosis in this setting was probably due to difficulties in establishing a diagnosis and due to the administration of prophylaxis with TMP/SMX, since such patients are also at risk for PCP.