Bordetella Pertussis Infection in Patients with Cancer Abraham Yacoub, MD, Sowmya Nanjappa, MD, Tyler Janz, and John N

Infectious Diseases Report

Bordetella pertussis Infection in Patients With Cancer Abraham Yacoub, MD, Sowmya Nanjappa, MD, Tyler Janz, and John N. Greene, MD

Summary: We illustrate 2 cases of pneumonia associated with Bordetella pertussis infection in 72-year-old and 61-year-old patients with cancer receiving myelosuppressive therapy after hematopoietic stem cell transplantation. Bacterial infections are a significant cause of morbidity and mortality in patients with cancer, and those receiving hematopoietic stem cell transplant, solid organ transplant, or myelosuppressive therapy are at increased risk. The infection was detected and the 2 patients had good outcomes following azithromycin treatment. Pertussis, also known as whooping cough, is a contagious respiratory illness that has become a public health challenge due to decreased immunity of the pertussis vaccine. Therefore, it is critical to recognize pertussis early in the course of the disease.

Introduction low sputum and shortness of breath associated with The lung is one of the most frequently involved or- the coughing spells. She had tried a cough suppressant gans in a variety of complications in the immunocom- with minimal relief. She denied fever, chills, sweats, promised host.1 Among the pulmonary complications hemoptysis, ill contacts, and recent travel. that occur in persons who are immunocompromised, Her vital signs were within normal limits, and infection is the most common and is associated with findings on physical examination were significant for high rates of morbidity and mortality.1 The most com- crackles heard throughout the lung fields. Her white monly encountered type of infection is bacterial in blood cell count was 4,910/µL with a normal differen- origin.2 Before the development of vaccines, Borde- tial. The patient denied receiving pneumocystis pro- tella pertussis infection was a significant threat among phylaxis in the past and tested negative for Pneumo- immunocompetent hosts.3 Bordetella vaccination has cystis jiroveci. significantly reduced the number of infections, but im- The result from a nasopharyngeal swab sent for munity appears to be short lived.4 In addition, a large a respiratory viral polymerase chain reaction (PCR) portion of the population remains susceptible to infec- panel was positive for B pertussis. PCR testing was tion from B pertussis.5 We present 2 cases of B pertussis negative for adenovirus, Chlamydia pneumoniae, infection that led to pneumonia in patients with cancer. coronavirus, metapneumovirus, rhinovirus, enterovi- The medical staff members at our institution were up rus, influenza types A and B, Mycoplasma, parainflu- to date on their vaccinations, and no secondary cases enza virus types 1 to 4, and respiratory syncytial virus. of pertussis were reported. Computed tomography (CT) of the chest showed dependent areas of subpleural consolidation and patchy, Case Reports ground-glass opacities (Fig 1). Case 1 She was discharged home with a 5-day course of A woman aged 72 years with metastatic ovarian can- oral azithromycin (250 mg daily). Repeat PCR testing cer who was receiving chemotherapy with intrathecal 1 week later was negative for B pertussis. She reported methotrexate, gemcitabine, and carboplatin presented improvement of her symptoms 3 weeks later. with a 12-day history of productive cough with yel- Case 2 A man aged 61 years admitted to our hospital with a From the Division of Infectious Diseases (AY, JNG) and Interna- tional Medicine (AY), Departments of Internal Medicine (SN) and 5-year history of chronic lymphocytic leukemia and Oncologic Sciences (SN), H. Lee Moffitt Cancer Center & Research a matched, unrelated donor stem cell transplantation Institute, and the Morsani College of Medicine (AY, SM, JNG), De- 12 days prior complained of a 1-day history of non- partment of Biomedical Sciences (TJ), University of South Florida, Tampa, Florida. productive cough, sore throat, and fatigue. He denied Submitted January 20, 2016; accepted March 5, 2016. fever, chills, shortness of breath, hemoptysis, nausea, Address correspondence to John N. Greene, MD, Department of vomiting, ill contacts, and recent travel. Infectious Diseases, Moffitt Cancer Center, 12902 Magnolia Drive, His vital signs were all within normal limits. Find- Tampa, FL 33612-9497. E-mail: [email protected] ing on physical examination was remarkable for coarse No significant relationships exist between the authors and the companies/organizations whose products or services may be ref- breath sounds heard across the left lung fields. His erenced in this article. white blood cell count was 560 µL, absolute neutrophil

April 2016, Vol. 23, No. 2 Cancer Control 163 Fig 1. — Computed tomography of the chest showing dependent areas of subpleural consolidation and patchy, ground-glass opacities. count was 190 µL, and lymphocyte count was 200 µL. The patient was receiving pneumocystis prophylaxis and tested negative for P jiroveci. The result from a nasopharyngeal swab sent for a respiratory viral PCR panel was positive for B pertussis. PCR testing was negative for adenovirus, C pneumoniae, coronavirus, metapneumovirus, rhinovirus, entero- virus, influenza types A and B, Mycoplasma, parainflu- enza virus types 1 to 4, and respiratory syncytial virus. Radiography of his chest showed an interval increase in opacification of the perihilar lungs. CT of his chest demonstrated patchy, bilateral airspace disease and ground-glass nodularity, which was greatest in the left lower lobe and bilateral small pleural effusions (Fig 2). Rapid strep testing was negative, and blood cultures did not show any growth after 3 days. He was treated with a 7-day course of oral azithro- Fig 2. — Computed tomography of the chest demonstrating patchy, bilateral airspace disease and ground-glass nodularity (greatest in the mycin (250 mg daily) and was followed-up in the clin- left lower lobe). ic. He reported complete resolution of his symptoms 2 weeks later. Repeat PCR testing for B pertussis per- formed on day 26 was negative. ratory tract. Evasion of host defenses is facilitated by adenylate cyclase toxin (CyaA) and pertussis toxin.12 Discussion CyaA enters the neutrophils and catalyzes the exces- B pertussis, a gram-negative aerobic, pleomorphic sive production of cyclic adenosine monophosphate, coccobacilli, is known to cause whooping cough, which intoxicates the cells such that phagocytosis which is a respiratory tract infection characterized is compromised. Similar to CyaA, pertussis toxin ad- by paroxysmal cough.6-9 B pertussis is transmitted by versely affects phagocytosis and inhibits the migra- large droplets produced during coughing, sneezing, tion of lymphocytes and macrophages to areas of in- or talking. These droplets generally travel fewer than fection.12 Local tissue damage of the ciliated epithelial 3 feet and can be deposited on mucosal surfaces of cells may be due to tracheal cytotoxin, dermonecrotic susceptible individuals.10 B pertussis belongs to the toxin, and perhaps CyaA.12 Bordetella genus, which now includes 9 species, and Although B pertussis mainly causes pulmonary B pertussis, B parapertussis, and B bronchiseptica are issues, it has been documented to be associated with the 3 most studied.11 otitis media,13 encephalopathy,14 bacteremia,15 he- Infection is initiated by the attachment of B per- molytic uremic syndrome,16-18 infantile hypertrophic tussis to the cilia of epithelial cells of the upper respi- pyloric stenosis,19 multiple sclerosis, amyotrophic

164 Cancer Control April 2016, Vol. 23, No. 2 lateral sclerosis,01 cerebral ataxia,21 and Wegener ated with prolongation of the QT interval.35 For pa- granulomatosis.22 tients allergic or intolerant to these agents, doxycycline Cough is one of the most common complaints or levofloxacin is an alternative option (rather than no among patients with B pertussis infection.23 Diagnosis treatment).35 If symptoms do not improve after a trial can be made by PCR assay because it is a rapid, effi- of macrolides, then resistance should be suspected.36,37 cient, and specific technique with superior sensitivity Use of vaccination against B pertussis has been compared with that of culture.24-26 well studied.38 The diphtheria, tetanus, and acellular Five other cases have been cited in the literature of pertussis (DTaP) vaccine is indicated only for children pertussis in patients with cancer and a mix of hemato- younger than 7 years of age.38 However, the adult teta- logical malignancies and solid tumors (Table).15,27-30 It nus, diphtheria, and acellular pertussis (Tdap) vaccine is worthy of note that these cases were published pri- is a 3-dose series with high tetanus and pertussis con- or the advent of PCR assay and several were based on tent that may be more immunogenic in recipients of culture of the organism from extrapulmonary sources hematopoietic stem cell transplantation, so it should (eg, blood, empyema fluid).15,27-30 be considered as the initial vaccination for this patient The recommended antimicrobial agents for the population, regardless of age.38 Furthermore, Suzuki treatment or chemoprophylaxis of pertussis in patients et al30 suggested that acellular pertussis vaccine can be who are immunocompromised or immunocompetent considered for patients after receiving hematopoietic are azithromycin, clarithromycin, and erythromycin.31 stem cell transplantation, even if they are adults or old- Trimethoprim/sulfamethoxazole can also be used.32 er than 7 years of age. Erythromycin, clarithromycin, and azithromycin are preferred for the treatment of pertussis in persons who Conclusions are at least 1 month of age.31 For infants younger than We presented 2 patients who had good outcomes fol- 1 month of age, azithromycin is preferred for postex- lowing azithromycin treatment. Due to the advent of posure prophylaxis and treatment because azithromy- and availability of polymerase chain reaction–based cin has not been associated with infantile hypertrophic diagnostic testing, the rate of Bordetella pertussis in- pyloric stenosis, unlike erythromycin.33,34 Azithromy- fection among patients who are immunocompromised cin should be used with caution because it is associ- and have cancer is expected to increase.39 Such test-

Table. — Studies of Bordetella pertussis Infection in Patients With Cancer Study Age, y Sex Malignancy Symptoms Source of Culture/ Treatment Outcome PCR Case 1 72 F Ovarian cancer Productive cough Pharynx Azithromycin Improved Shortness of breath PCR assay Case 2 61 M Chronic lymphocytic Nonproductive cough Pharynx Azithromycin Improved leukemia Sore throat PCR assay Fatigue

Florax27 16 M ALL Nonproductive cough Pharynx Roxithromycin Symptoms resolved PCR after 2 mo of treatment MacLean29 — — Bronchogenic lung — — — — cancer Senturk28 64 F Non–small-cell lung Dyspnea Empyema Erythromycin 2 mg/d Improved cancer Chest pain PCR assay Suzuki30 10 M ALL Dry cough Plasma serum Cephalosporin Poor Sleep disturbances PCR assay Clarithromycin Troseid15 63 M Multiple myeloma Cough Blood culture Clarithromycin Poor Hoarseness Fever

ALL = acute lymphoblastic leukemia, F = female, M = male, PCR = polymerase chain reaction.

April 2016, Vol. 23, No. 2 Cancer Control 165 ing can be easily done via a nasopharyngeal swab. 2012;48(7):263-264. 29. MacLean DW. Bordetella pertussis infection in patients with bron- The literature is scant regarding pertussis in chogenic carcinoma. Lancet. 1981;1(8218):503-504. adults — and this is particularly true among those 30. Suzuki N, Mizue N, Hori T, et al. Pertussis in adolescence after unrelated cord blood transplantation. Bone Marrow Transplant. 2003;32(9):967. with cancer — due to the historical difficulty of accu- 31. Dierig A, Beckmann C, Heininger U. Antibiotic treatment of pertussis: rate diagnostic testing.39 are 7 days really sufficient? Pediatr Infect Dis J. 2015;34(4):444-445. 32. Altunaiji S, Kukuruzovic R, Curtis N, et al. Antibiotics for whooping cough (pertussis). Cochrane Database Syst Rev. 2007;(3):CD004404. References 33. Cooper WO, Griffin MR, Arbogast P, et al. Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis. Arch Pediatr Adolesc 1. Oh YW, Effmann EL, Godwin JD. Pulmonary infections in immuno- Med. 2002;156(7):647-650. compromised hosts: the importance of correlating the conventional radio- 34. Santos N, Oliveira M, Galrinho A, et al. QT interval prolongation logic appearance with the clinical setting. Radiology. 2000;217(3):647-656. and extreme bradycardia after a single dose of azithromycin [in English, 2. Conces DJ Jr. Bacterial pneumonia in immunocompromised patients. Portuguese]. Rev Port Cardiol. 2010;29(1):139-142. J Thorac Imaging. 1998;13(4):261-270. 35. Flanagan MP. How to manage a pertussis outbreak in your practice. 3. Hewitt M, Canning BJ. Coughing precipitated by Bordetella pertussis Fam Pract Manag. 2005;12(7):31-34. infection. Lung. 2010;188(suppl 1):S73-S79. 36. Guillot S, Descours G, Gillet Y, et al. Macrolide-resistant Bordetella 4. Ward JI, Cherry JD, Chang SJ, et al; APERT Study Group. Borde- pertussis infection in newborn girl, France. Emerg Infect Dis. 2012;18(6):966-968. tella pertussis infections in vaccinated and unvaccinated adolescents and 37. Lewis K, Saubolle MA, Tenover FC, et al. Pertussis caused by an adults, as assessed in a national prospective randomized Acellular Pertus- erythromycin-resistant strain of Bordetella pertussis. Pediatr Infect Dis J. sis Vaccine Trial (APERT). Clin Infect Dis. 2006;43(2):151-157. 1995;14(5):388-391. 5. Bloom DE. The value of vaccination. Adv Exp Med Biol. 2011;697:1-8. 38. Rubin LG, Levin MJ, Ljungman P, et al; Infectious Diseases Society of 6. Shumilla JA, Lacaille V, Hornell TM, et al. Bordetella pertussis infec- America. 2013 IDSA clinical practice guideline for vaccination of the immu- tion of primary human monocytes alters HLA-DR expression. Infect Immun. nocompromised host [Erratum appears in Clin Infect Dis. 2014;59(1):144]. 2004;72(3):1450-1462. Clin Infect Dis. 2014;58(3):e44-e100. 7. Skerry CM, Mahon BP. A live, attenuated Bordetella pertussis vac- 39. McGuiness CB, Hill J, Fonseca E, et al. The disease burden of per- cine provides long-term protection against virulent challenge in a murine tussis in adults 50 years old and older in the United States: a retrospective model. Clin Vaccine Immunol. 2011;18(2):187-193. study. BMC Infect Dis. 2013;13:32. 8. Greenberg D, Bamberger E, Ben-Shimol S, et al. Pertussis is under diagnosed in infants hospitalized with lower respiratory tract infection in the pediatric intensive care unit. Med Sci Monit. 2007;13(11):CR475-CR480. 9. Bettiol S, Thompson MJ, Roberts NW, et al. Symptomatic treatment of the cough in whooping cough. Cochrane Database Syst Rev. 2010;(1):CD003257. 10. Sandora TJ, Gidengil CA, Lee GM. Pertussis vaccination for health care workers. Clin Microbiol Rev. 2008;21(3):426-434. 11. Guiso N. Bordetella pertussis and pertussis vaccines. Clin Infect Dis. 2009;49(10):1565-1569. 12. Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin Microbiol Rev. 2005;18(2):326-382. 13. Decherd ME, Deskin RW, Rowen JL, et al. Bordetella pertussis causing otitis media: a case report. Laryngoscope. 2003;113(2):226-227. 14. Halperin SA, Marrie TJ. Pertussis encephalopathy in an adult: case report and review. Rev Infect Dis. 1991;13(6):1043-1047. 15. Trøseid M, Jonassen TØ, Steinbakk M. Isolation of Bordetella pertussis in blood culture from a patient with multiple myeloma. J Infect. 2006;52(1):e11-e13. 16. Cohen-Ganelin E, Davidovits M, Amir J, et al. Severe Bordetella pertussis infection associated with hemolytic uremic syndrome. Isr Med Assoc J. 2012l;14(7):456-458. 17. Chaturvedi S, Licht C, Langlois V. Hemolytic uremic syndrome caused by Bordetella pertussis infection. Pediatr Nephrol. 2010;25(7):1361-1364. 18. Pela I, Seracini D, Caprioli A, et al. Hemolytic uremic syndrome in an infant following Bordetella pertussis infection. Eur J Clin Microbiol Infect Dis. 2006;25(8):515-517. 19. Morrison W. Infantile hypertrophic pyloric stenosis in infants treated with azithromycin. Pediatr Infect Dis J. 2007;26(2):186-188. 20. Flore D. Diagnosis and treatment of multiple sclerosis and amyotrophic lateral sclerosis: neuropathies from Bordetella pertussis. Am J Ther. 2003;10(5):377-379. 21. Setta F, Baecke M, Jacquy J, et al. Cerebellar ataxia following whooping cough. Clin Neurol Neurosurg. 1999;101(1):56-61. 22. Janda WM, Santos E, Stevens J, et al. Unexpected isolation of Borde- tella pertussis from a blood culture. J Clin Microbiol. 1994;32(11):2851-2853. 23. Melo N, Dias AC, Isidoro L, et al. Bordetella pertussis, an agent not to forget: a case report. Cases J. 2009;2(1):128. 24. van der Zee A, Agterberg C, Peeters M, et al. A clinical validation of Bordetella pertussis and Bordetella parapertussis polymerase chain reaction: comparison with culture and serology using samples from patients with suspected whooping cough from a highly immunized population. J Infect Dis. 1996;174(1):89-96. 25. Birkebaek NH, Heron I, Skjødt K. Bordetella pertussis diagnosed by polymerase chain reaction. APMIS. 1994;102(4):291-294. 26. Gilberg S, Njamkepo E, Du Chatelet IP, et al. Evidence of Bor- detella pertussis infection in adults presenting with persistent cough in a French area with very high whole-cell vaccine coverage. J Infect Dis. 2002;186(3):415-418. 27. Florax A, Ehlert K, Becker K, et al. Bordetella pertussis respiratory infection following hematopoietic stem cell transplantation: time for univer- sal vaccination? Bone Marrow Transplant. 2006;38(9):639-640. 28. Senturk E, Sen S, Telli M. Empyema due to Bordetella pertussis in an adult patient with lung cancer [in English, Spanish]. Arch Bronconeumol.

166 Cancer Control April 2016, Vol. 23, No. 2