Nonneutropenia Phase (Pre- and PostTherapy)

The newly diagnosed patient with cancer prior to chemotherapy and those between cancer therapies have a relatively intact and functional immune system. The primary respiratory infections in this relatively nonimmunocompromised phase include those caused by pathogens common to the general public. The predominant organisms are Streptococcus pneumoniae, Haemophilis influenzae, and community-acquired respiratory viruses (Table 153-1) such as influenza, parainfluenza, respiratory syncytial virus, and adenovirus. The presentation of respiratory tract infections at this phase (sinusitis, bronchitis, pneumonia), whether viral or bacterial, is similar to that in patients without cancer. However, the duration of illness may be longer and the possibility of a serious complication such as bacteremia, sepsis, or adult respiratory distress syndrome may be greater in the cancer patient. The treatment of bacterial community-acquired respiratory infections is the same as in noncancer patients with new generation macrolides (azithromycin and clarithromycin), new generation fluroquinolones (levofloxacin, gatifloxacin, moxifloxacin) or amoxicillin or amoxicillin/clavulanate (for penicillin-sensitive isolates). Outpatient oral therapy with these agents can be given for from 5 to 14 days. Intravenous third-generation cephalosporins (cefotaxime, ceftriaxone) or the aforementioned fluoroquinolones can be given to the sick hospitalized patient for coverage of S. pneumoniae or H. influenzae. The addition of an anti-pseudomonal B lactam antibiotic (piperacillin plus tazobactam or ticarcillin plus clavulanate) may be necessary for the critically ill cancer patient at this phase because of a greater chance of oropharyngeal colonization with gram-negative bacilli (Table 153-2). In addition, the seriously ill may require a fluroquinolone for coverage of Legionella, which occurs more commonly in cancer patients.

Table 153-1

Community Acquired Respiratory Viruses.

Table 153-2

Gram-Negative Bacilli (GNB).

Some patients are prone to respiratory infections because of the immune dysregulation caused by their cancers, such as multiple myeloma and chronic lymphocytic leukemia, or from asplenia. Due to defective humoral immunity, the encapsulated organisms such as pneumococcus and H. influenzae commonly cause sinusitis, otitis, bronchitis and pneumonia during this pretreatment phase. Penicillin-resistant pneumococcus is increasing in prevalence and is particularly predominant in the cancer patient; 5 of 6 (83%) of isolates at H. Lee Moffitt Cancer Center in 2001. At commonly used doses, penicillin, ampicillin and amoxicillin are not effective against these strains.

Because of universal nationwide vaccination with HIB (H. influenzae B) vaccine in children, invasive HIB in adults, including cancer patients, has significantly declined. However, a proportionate increase in nontypable Haemophilus has been found, albeit less virulent than HIB. Forty percent of Haemophilus make β-lactamase; therefore, penicillin antibiotics (without a βlactam inhibitor combination such as in amoxicillin/clavulanate) can be rendered ineffective. New generation quinolones and second-generation cephalosporins (cefuroxime, cefaclor) remain effective against Haemophilus as well as pneumococcus.

Patients with lung cancer present with two potential risk factors for developing respiratory infections; namely, bronchial airway obstruction by tumor and the frequent association of chronic obstructive pulmonary disease (COPD). The presence of the former leads to post obstructive pneumonia and the latter to a predisposition for pneumococcus, H. influenzae, Moraxella influenzae, other respiratory viruses, and atypical pathogens (Mycoplasma and Chlamydia) inducing COPD exacerbations.

Postobstructive pneumonia over weeks to months frequently becomes necrotizing, with chronic lung volume loss and secondary cavity formation. The initial pathogens are virulent bacteria such as Pseudomonas aeruginosa and other gram-negative bacilli (see Table 153-2), upper respiratory anaerobes, and Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]). The duration of antibiotic treatment is 6 weeks to 3 months, depending on the clinical response. Antimicrobials of choice need to cover the aforementioned pathogens and include intravenous piperacillin/tazobactam, carbapenems (imipenem/cilastain or meropenem), or cefepime, or ciprofloxacin in combination with clindamycin. Oral therapy consists of ciprofloxacin combined with amoxicillin/clavulanate or clindamycin. Treatment of the cancer includes radiation, chemotherapy, or laser therapy to relieve the obstruction or surgical resection of the involved lung when possible.

After 4 to 8 weeks, when further necrosis causes a cavity, and after prolonged antimicrobial therapy, resistant gram-negative bacilli, MRSA, anaerobes and molds, especially Aspergillus, become the predominant pathogens. Not infrequently, the progressing cancer in the necrotic lung can confound treatment and be impossible to distinguish from ongoing infection short of a biopsy of the affected area. Treatment at this stage includes further efforts to relieve obstruction when possible, along with appropriate antimicrobials. Antibiotic therapy usually is long term intravenous (IV) cefepime or meropenem with or without vancomycin or clindamycin. Mold therapy requires resection when possible and long-term (6 wk to indefinite), voriconazole (IV or PO), itraconazole (IV or PO), Cancidas (only IV), or lipid formulations of amphotericin B (only IV).¹

Vaccination for pneumococci and H. influenzae type B should be given to patients with lung cancer, multiple myeloma, and chronic lymphocytic leukemia even though the immune response will be less than that of the general population. Prophylactic antibiotics are not routinely given to prevent infections with these organisms.

Patients receiving chronic corticosteroid therapy (> 1 mo of prednisone at a dose of ≥ 20 mg) in this phase of their illness have the added risk of acquiring Pneumocystis carinii pneumonia (PCP), especially when steroids are tapered. PCP develops primarily in patients with acute and chronic lymphocytic leukemia, lymphomas, and solid tumors receiving chronic corticosteroids. Besides corticosteroids, other drugs that predispose to PCP include fludarabine, campath antibodies, and cyclosporine.² Following a therapeutic course of intravenous trimethoprim/ sulfamethoxazole, prophylaxis with the same agent orally (PO) is usually required for 6 months or longer to prevent recurrence. Other less common opportunistic infections related to chronic steroid use include Nocardia, Legionella, Mycobacterium, cytomegalovirus (CMV) and fungi (including molds such as Aspergillus and endemic mycoses) (Tables 153-3 and 153-4).^{2, 3, 4}

Table 153-3

Mycobacterium.

Table 153-4

Fungi.

Neutropenia Phase

Neutropenia can be divided into three distinct periods; short term (< 1 wk), mid-term (1–2 wk) and long term (> 2 wk) with different infections occurring at each time. The use of prophylactic antimicrobials will alter the infection risk during the first two time periods. In the 1960s to 1980s, gram-negative bacilli predominated as the cause of pneumonia and bacteremia in febrile neutropenic patients. From the 1990s to present, the use of prophylactic trimethoprim/sulfamethoxazole or fluroquinolones and early empiric antibiotic therapy with gram-negative activity has resulted in a shift from gram-negative bacilli to gram-positive causative organisms. Catheter-related and mucositis-related bacteremia make up the majority of the gram-positive infections. Pneumonia caused by gram-positive bacteria (except for S. aureus and S. pneumoniae) is unusual.

Pneumonia occurring during the first week of neutropenia is predominately due to gram-negative bacilli such as P. aeruginosa and Enterobacteraceae. S. pneumoniae is the predominant gram-positive organism. Bacteremia in conjunction with pneumonia during this period is due to P. aeruginosa or S. pneumoniae, with a higher morality (55%) than bacteremia not related to pneumonia (11%).⁵ A combination of an anti-pseudomonal B lactam antibiotic combined with an aminoglycoside or fluroquinolone is the preferred treatment regimen. If prophylactic fluroquinolones are used before or during the first week of neutropenia, bacterial pneumonia would be unusual. Neutropenia does not increase the risk of infection with pneumococci, H. influenzae, Legionella, or viral respiratory pathogens. However, during wintertime, community outbreaks of influenza virus and respiratory synctial virus (RSV) can cause severe pneumonia and death in neutropenic leukemic patients who recently received chemotherapy.⁶

The second period of neutropenia, from 7 to 14 days, is a transition period when predominant pathogens are these also found in both the short- and long-term periods. The selective pressure of antibiotics for greater than one week with activity against gram-negative bacilli and S. aureus results in the appearance of resistant gram-negative bacilli such as the “SPACE” organisms and molds (see Table 153-2). Empiric combination therapy against gram-negative bacilli during the first week of neutropenia may prevent the emergence of the SPACE pathogens. Pneumonia suspected to be caused by SPACE organisms should be treated with a carbapenem combined with an aminoglycoside or quinolone. Monotherapy with ceftazidime, aztreonam, ticarcillin/clavulanate, piperacillin/tazobactam could select for a SPACE organism due to inducible B lactamase production. Cefepime and carbapenems are effective in preventing the emergence of SPACE pathogens. The duration of therapy is for at least 2 weeks or longer if neutropenia persists.

Empiric antifungal therapy directed against molds should be considered during day 10 to 14 of neutropenia to avoid the development of mold pneumonia. The high mortality, the need for prolonged therapy, and the high incidence of recurrent infection during future periods of neutropenia make prevention of mold pneumonia of paramount importance. Mold pneumonia is treated with medical therapy and surgical resection if solitary lobar consolidation is present and the patient is a suitable surgical candidate. Medical therapy includes lipid formulations of amphotericin B, Cancidas, itraconazole, or voriconazole, alone or in combination. The duration of therapy is for 6 weeks to 6 months, depending on resolution of the infection. Early reinstitution of antifungal therapy is warranted with future episodes of prolonged neutropenia.

Infections due to Candida spp. usually begin after seven days of neutropenia and usually consist of mucosal disease, urinary tract infection, or candidemia. Candida pneumonia is an uncommon entity. On the other hand, Candida colonization of the upper respiratory tract is quite common in patients with cancer. Most cases of Candida cultured from sputum or bronchoalveolar lavage is due to upper airway colonization and not pneumonia.⁷ True Candida pneumonia presents as lower lobe nodular (1–2 cm) lesions in the lung found in conjunction with disseminated disease in other organs such as liver, spleen, or kidney. Candidemia occurs in only 50% of cases of disseminated candidiasis. Diagnosis requires lung biopsy, or demonstration of elevated ratios of d to l arabinitol in serum or urine, but both methods are usually deferred and empiric treatment is undertaken on the basis of the characteristic clinical presentation.⁸ Treatment consists of fluconazole, itraconazole, voriconazole, amphotericin B or its lipid formulations, or Cancidas depending on the species of Candida. The duration is usually 6 weeks to 3 months or more depending on radiographic resolution.

The third period of prolonged neutropenia of 14 days or longer provides a unique challenge to prevent the development of pneumonia. The predominant pathogens are resistant gram-negative bacilli (“SPACE pathogens”) and molds. The predominant mold is Aspergillus fumigatus with other species of Aspergillus following in frequency. Treatment of Aspergillus pneumonia is mentioned above. Emerging molds also occur during this period, especially as the period of neutropenia lengthens and the use of amphotericin B formulations increases. These molds are relatively resistant to amphotericin B and include Fursarium spp. and Scedosporium spp. Voriconazole is the drug of choice for these latter two fungal pathogens. Renal and hepatic dysfunction, allergic reactions, other dose limiting side effects, ease of administration, cost, and duration of therapy are important considerations when choosing appropriate antifungal therapy. Noninfectious causes of pulmonary infiltrates are common and can mimic the aforementioned infections (Table 153-5).

Table 153-5

Non-Infectious Causes of Pulmonary Infiltrates.

Post-Engraftment Phase (Following Allogeneic Stem Cell Transplantation)

The post-engraftment phase following allogeneic stem cell transplantation (SCT) can be divided into early (engraftment to 100 days) and late (over 100 days) periods with similar pathogens but different levels of risk for some organisms. Pneumonia complicates half of all SCTs, with no specific etiology found in one-third of cases. The predominant causes of pneumonia in the early phase of post-engraftment depends on the degree of immunosuppression from the treatment of acute graft-versus-host disease and the sustenance of the new stem cells engrafted. Cellular immune dysfunction occurs in both periods and leads to a variety of opportunistic infections. Noninfectious causes of pulmonary infiltrates predominate, with idiopathic interstitial pneumonia, bronchiolitis obliterans with organizing pneumonia (BOOP), and diffuse alveolar hemorrhage (DAH) being the most important. Infectious causes can be differentiated based on the acuteness of the presenting symptoms and the appearance of the pulmonary infiltrates (Table 153-5 points a, b, c).

Acute presentations warrant consideration of resistant gram-negative bacilli (SPACE pathogens), Legionella, viruses (such as CMV, human herpesvirus 6 [HHV-6], community-acquired respiratory viruses), pulmonary emboli, and pulmonary edema. Subacute or chronic presentations point to opportunistic pathogens such as fungi, most commonly, followed by endemic mycoses, Cryptococcus, Mycobacterium, and Nocardia (see Tables 153-3 and 153-4). The overall 1-year survival rate for patients infected with fungi following SCT was 20%, with an increase over the last decade of non-fumigatus Aspergillus species, Fusarium, and Zygomycetes.^{9, 10} The noninfectious causes with a similar presentation include BOOP and pulmonary emboli with lung infarction.

Interstitial or reticulonocular infiltrates best seen with a high resolution computed tomography (CT) scan of the lungs bring to mind viral infections that are reactivated (CMV or HHV-6) or exogenously acquired (RSV, influenza, parainfluenza, adenovirus), PCP, Legionella, and Mycobacteria. Although rare, Mycobacterium avium intracellulare or rapidly growing Mycobacterium should be suspected when bronchiectasis and anterior lower lung nodules (1–2 cm) are seen.⁴ Reactivated or primary M. tuberculosis pneumonia is rare as well but could present with a variety of pulmonary infiltrate patterns. Noninfectious causes such as idiopathic interstitial pneumonia, BOOP, DAH and drug-induced pneumonitis require high-dose steroids. Frequently, empiric antimicrobials are combined with steroids especially in the critically ill patient while diagnostic procedures to determine the etiology are ongoing, including bronchoscopic sampling, blood sampling, and occasionally open lung biopsy.

Weekly CMV antigen detection of blood has virtually eliminated CMV pneumonia because of early institution of pre-emptive CMV therapy (valganciclovir orally or ganciclovir or foscarnet intravenously) maintained for 3 weeks or longer. HHV-6 induced interstitial pneumonia is usually diagnosed with polymerase chain reaction (PCR) of blood and treated with the aforementioned CMV treatment regimens. The community acquired respiratory viruses are not usually treated except for influenza virus (with rimantadine or the new neuroaminadase inhibitors), and RSV treatment includes intravenous RSV Ig with or without inhaled ribavirin. Treatment of severe parainfluenza virus or adenovirus usually is ineffective, but intravenous ribavirin has been used successfully in a few cases. The community-acquired respiratory viral infections in SCT recipients at one cancer center included parainfluenza (30%), rhinovirus (25%), and influenza (11%).¹¹ Pneumonia occurred in 49% with RSV, 22% with parainfluenza, 10% with influenza, and 3% with rhinovirus. Lower respiratory tract infections with parainfluenza are associated with a high mortality following SCT (100% [6 of 6] in one series).¹² In another series of bone marrow transplant (BMT) recipients, parainfluenza pneumonia had a 20% mortality rate, whereas the rate for RSV was 60%, adenovirus 75%, and influenza 17%.¹³

Dense consolidation or nodular infiltrates larger than 2 cm usually indicate mold infection or gram-negative bacilli. Cavitary infiltrates are usually caused by molds. Other less common causes include Nocardia, Mycobacterium, endemic mycoses, Rhodococcus, and the underlying malignancy itself.

The late period following stem cell engraftment may see the same causes of pulmonary infiltrates as the early period, especially if immunosuppressive therapy is needed for chronic graft-versus-host disease. Mold-induced pneumonia, idiopathic interstitial pneumonia, and BOOP are most common. Molds include all of the aforementioned isolates. However, Zygomycetes (especially Mucorales and Rhizopus) warrant further consideration. These pathogens require exogenous iron for growth and favor the patient overloaded with iron from multiple transfusions who may be receiving desferoxamine. Zygomycetes infections are treated with lipid formulations of amphotericin B. Cancidas and all the azoles show resistance except posaconazole (not FDA approved). Pneumococcal pneumonia may occur during this period because of the persistence of a defective humoral immunity. Disseminated varicella, herpes simplex virus, and the community-acquired respiratory viruses may cause pneumonia as well.

In summary, when evaluating pneumonia in patients with cancer, determining the level of immunosuppression, the previous exposure to antimicrobials (over the last month), the duration of the illness, the presenting symptoms, and the radiographic pattern will better predict the suspected pathogens or noninfectious causes. Following this determination, the appropriate antimicrobials can be instituted empirically. Knowing the three phases of cancer therapy and their associated respiratory complications should improve the accuracy of predicting the etiology of pulmonary pathology.