CARDIAC DIPHTHERIA IN A PREVIOUSLY IMMUNIZED INDIVIDUAL Loreli Munford, MD; Jennifer Jones, MD; Lorena Landrum, MD; John O'Connell, MD; and Eric Ayers, MD Virginia and Detroit, Michigan
A previously healthy 19-year-old Asian female without significant past medical history presented to the emergency room complaining of a sore throat, difficulty in swallowing, fever, swollen neck, malaise, and myalgia for three to four days. The patient was initially seen at an outside hospital, evaluated by an ear, nose, and throat physician (ENT), and was found to have desquamative pharyngitis. The patient was transferred to our hospital after she continued to experience progressively worsening shortness of breath and went into acute respiratory distress. The patient was found to have laryngeal edema on exam with greenish-black, necrotic-looking tissue extending to the hypopharynx, nasopharynx, and oropharynx. A culture was taken. ENT was consulted for tracheostomy placement. The patient refused to have tracheostomy placed. She went into severe respiratory distress and required urgent tracheostomy. A cardiac consult was obtained. A 2D echocardiogram performed one day after admission revealed an ejection fraction (EF) of 10-20%, normal left ventricular cavity size, normal wall thickness, and severe global systolic dysfunction. There was mild to moderate mitral regurgitation and trace tricuspid regurgitation. The inferior vena cava was dilated and a 1 cm x 1.5 cm questionable mass or thrombus was seen. The patient's throat culture was positive for diphtheria. The CDC was contacted, and the patient was treated with antitoxin with prompt resolution of cardiac symptoms. A repeat echo done five days post-treatment showed improved EF of 65%, normal left ventricular thickness and function, with no clot visualized. She was treated with ceftriaxone and flagyl for ocular motor neuritis, otitis media, and strep. pneumonia with gradual improvement. These were all secondary to the diphtheria toxins, however, the patient continues to be followed as an outpatient by ENT for ongoing problems with swallowing, speech, and trach management. (J Natl Med Assoc. 2003;95:875-878.)
Key words: diphtheria * immunization + antitoxin © 2003. From the Medical College of Virginia, Virginia Commonwealth University (Munford); Division of Cardiology (Jones, fellow); Detroit Community Health Connection (Landrum); Department of Internal Medicine, Wayne State University School of Medicine (O'Connell, director, internal medicine); and Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine (Ayers, director, med/peds). This case was presented at a research seminar, Wayne State University School of Medicine, April 25, 2002. Send correspondence and reprint requests for J Natl Med Assoc. 2003;95:875-878 to: Eric Ayers, MD, 4201 St. Antoine, UHC-5C, Detroit, Ml 48201; phone: (313) 577-4342; fax: (313) 745-4707; e-mail:
[email protected]
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While cardiac diphtheria is commonly seen in third world countries in unimmunized individuals, it is very uncommon in the U.S. This is the second CDC-reported case in a previously immunized individual. This patient received her scheduled diphtheria, pertusis, and tetanus (DPT) immunizations on a delayed basis. Her first DPT was administered at age five. She received a total of three doses of DPT at two-month intervals, with her final dose of DPT given the subsequent year. It is possible that the manner in which the patient was immunized contributed to her susceptibility in contracting this disease. There is no other explanation that addresses or answers the question as to why a healthy, young VOL. 95, NO. 9, SEPTEMBER 2003
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Asian-American female with no history of HIV or other immunodeficiency contracted such an unusual disease in the United States.
Case Presentation A previously healthy 19-year-old Asian female without significant past medical history presented to the emergency room complaining of a sore throat, difficulty in swallowing, fever, swollen neck, malaise, and myalgia for three to four days. She denied any recent sick contacts.
Immunization Record 5/8/87: DPT #1, 7/8/87: DPT #2, 9/8/87: DPT #3, 9/8/87: Polio #1 and #2, 5/18/88: DPT #4, and 5/18/88: Polio #3.
Physical Exam General exam revealed a lethargic appearing female. Head and neck exam was significant for tender cervical lymph nodes. Her tympanic membranes were normal. Orophamyx contained a homogeneous desquamating exudative greenish-black membrane. The regions of the mouth and nose that were involved include the orophamyx, hypopharynx, and nasopharnx with extension to the subglottic region. The lung exam was normal. Cardiac exam revealed a normal Sl and S2 without a rub or murmur. Abdominal exam was benign. The extremity exam was negative for cyanosis and edema. The neurological exam was normal.
Hospital Course The patient was transferred from North Oakland Hospital to the Detroit Medical Center (DMC) after evaluation of her pharynx. Due to severe edema and obstruction, the patient was offered a tracheostomy, but refused. Prior to transfer, the patient received ceftriaxon, ampicillin/sulbactrim, and gentamycin for her pharyngitis symptoms. Upon arrival, the patient was found to have difficulty breathing. Her vital signs were BPI 17/68 P 138 R 36 T 98.4. Oxygen saturation was 100% on 4 liters/min. of nasal oxygen. Due to continued respiratory distress, the patient agreed to have a tracheostomy. Post-observation day #1 vital signs were: Pulse 120-150 (sinus tachycardia on monitor) BP 90/60 Temp. 103. Pertinent physical findings were tracheostomy collar in place with ventilatory oxygen support. Diffuse facial swelling was noted with a bull neck appearance. The lungs were clear. The cardiac exam showed muffled heart JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
sounds with no clicks, rubs, or murmurs. The patient had a brisk carotid upstroke and was sedated. The patient was then admitted to the MICU due to worsening respiratory status. Mechanical ventilation was required along with respiratory isolation. The patient was seen by the cardiology consult team due to worsening cardiac function. A 2D echo was performed. A pulmonary catheter (PA cath.) was placed to monitor hemodynamics. The 2D echo revealed a mildly dilated left ventricle with severe left ventricular dysfunction, global hypokinesis, and mild mitral regurgitation with EF of 15-20%. At this time, the patient was being supported with inotropic therapy. Hemodynamics included a pulmonary capillary wedge pressure (PCWP) 18-20, cardiac output 4 liters/min. with a systemic vascular resistance (SVR) of 748. The patient was thought to be in either cardiac tamponade, cardiogenic shock with myocarditis, or septic shock. Infectious Disease was consulted and antibiotics were started for sepsis and pharyngitis. (erythromycin 500 mg IV q 6 hrs and ampillicin/sulbactrim 3 mg IV q 6 hrs). Serology was obtained for diphtheria toxin. Antitoxin was given. The patient was tested for allergic reaction to antitoxin prior to administration of the antitoxin. Additional work-up included an immunologic work-up which was negative and hematology/oncology consult for neutropenia and coagulopathy due to possible sepsis. Five days after antitoxin administration, a repeat 2D echo revealed improved EF of 65% with normal left ventricular size, function, and thickness. It was felt that the improved cardiac function was most likely due to treatment for diphtheria with antitoxin and antibiotics. Speech pathology was asked to evaluate the patient for dysphagia and pharyngeal edema. A feeding tube was placed to bypass the obstructive process in her oral pharyngeal airway. She received ceftriaxone and flagyl for ocular motor neuritis, otitis media, and strep. pneumonia. The patient improved and was discharged.
Outpatient Course The patient was followed by ENT. Initially, the patient was able to talk after her acute illness. She subsequently lost this ability by six weeks post-discharge. She was readmitted. She underwent esophagoscopy, esophageal dilation, and laryngeal airway dilation done. Several stents were placed in her airway to maintain patency. The 2D echo in one re-admission revealed an ejection fraction of 70%. VOL. 95, NO. 9, SEPTEMBER 2003
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Labs
Pathology and Pathogenesis
Blood cultures from North Oakwood were positive for strep. pneumonia. Her throat culture was positive for diphtheria. She had a positive tissue culture for strep. viridian group.
Toxin contributes locally to pseudomembrane formation. Systemically, it can cause myocarditis, neuritis, and focal necrosis in various organs, including the kidneys, liver, and adrenal glands. Changes in the myocardium include cloudy swelling of muscle fibers and interstitial edema. Thus, diphtheria can cause permanent cardiac damage.
Definition Diphtheria is a localized infection of mucous membranes or skin caused by Corynebacterium diphtheriae, which may be characterized by a pseudomembrane.
Etiology C. diphtheriae is an aerobic, nonmotile, non-
sporulating, irregularly staining, gram positive rod.
Immunology Diphtheria toxin is converted to a nontoxic but immunogenic product (diphtheria toxoid) when treated with formaldehyde. Immunity is conferred when antitoxin titers are >0.01 unit per milliliter. The incubation period for respiratory diphtheria is typically two to five days and rarely up to eight days.
Diagnosis Clinical: A characteristic pseudomembrane on the mucous of the tonsils, palate, oropharynx, nasopharynx, nose, or larynx suggests diphtheria. However, the diphtheria pseudomembranes must be distinguished from other pharyngeal exudates, including those of group A j3-hemolytic streptococcal infections, infectious mononucleosis, viral pharyngitis, fusospirochetal infection, and candidiasis. Diphtheria should be considered in patients with sore throat, cervical adenopathy, swelling, lowgrade fever, especially when these manifestations are accompanied by systemic toxicity, hoarseness, stridor, and palatal paralysis. Primary isolates can be screened rapidly for the presence of the tox genes by polymerase chain reaction, although occasional strains of C. diphtheriae that carry an inactive toxin gene give false-positive results.
Treatment Antitoxin should be given as soon as clinical diagnosis of diphtheria is made. Isolates are often susceptible to a variety of antimicrobials, including penicillins, cephalosporins, erythromycin, and tetracycline. Erythromycin has been the most effiective to date in the treatment of diphtheria.
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Clinical Manifestations Patients with C. diphtheriae in the respiratory tract are classified as diphtheria cases if pseudomembranes are present and as diphtheria carriers if pseudomembranes are absent. The disease is graded as tonsillar if pseudomembranes are localized to the tonsils, as combined types or delayed diagnosis if more extensive pseudomembranes are present, and as severe if cervical adenopathy or cervical edema is also present. Onset is often gradual, but most patients seek medical care within a few days of becoming ill. Fever of 37.8-38.9 degrees C (100- 102 degrees F), sore throat, and weakness are the most common symptoms, while dysphagia, headache, and change of voice occur in fewer than half of patients. Systemic manifestations are due primarily to toxic effects of diphtheria toxin. Non-toxic: discomfort and malaise. Toxic: listlessness, pallor, tachycardia, and vascular collapse. Respiratory tract infection is usually tonsillopharyngeal but may also be (in decreasing order) laryngeal, nasal, and tracheobronchial.
Epidemiology The CDC continues to conduct surveillance for diphtheria and other vaccine-preventable illnesses, to guard against the ever-present possibility oftheir reemergence. Most new cases are imported. In 1996, researchers isolated strains of toxigenic C. diphtheriae from throat swabs and blood samples obtained from several members of a small community in South Dakota who had mild or asymptomatic infections. Molecular analysis ofthe bacterial strains suggested that they were endemic, rather than imported. CDC recommends that all Americans receive a diphtheria booster every 10 years.
CONCLUSION While cardiac diphtheria is commonly seen in third world countries in unimmunized individuals, it is very uncommon in the U.S., as this is the second VOL. 95, NO. 9, SEPTEMBER 2003
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CDC-reported case in a previously immunized individual since 1999. In 1997 (MMWR 97:46: 506-10), four cases of diphtheria were reported in the U.S. However, two of these cases occurred in persons fully immunized, evident by localized mild illness. Fully immunized individuals can become infected with C. diphtheria because the antibodies are directed only against the toxin, and antitoxin neither prevents colonization by C. diphtheria nor eradicates the carrier state. Yet the disease is mild. Serious infection and death occur only in unimmunized or incompletely immunized individuals. Hence, it is possible that the manner in which the patient was immunized contributed to her susceptibility. Food for thought: Is this a new strain of C. diphtheria that is unaffected by current vaccinations? Is this case representative of a new focus of endemic infection evolving in Michigan? Is this case reflective of failure of complete immunization? To ascertain
the answer to these questions, we are currently trying to obtain banked blood to analyze for C. diphtheria IgG. Ifthe IgG is negative, then this patient was never immunized against the current strains of infection, in spite of obtaining a full course of immunizations, and this may indicate the emergence of a new strain. If the IgG is positive, then this implies that the patient was incompletely immunized.
REFERENCES 1. Havaldar PV, Sankpal MN, Doddannavar, RP (2000) Diphtheritic myocarditis: clinical and Laboratory parameters of prognosis and fatal Outcome. Annals of Tropical Paediatrics 20:209-15. 2. Loukoushkina, EF, Bobko PV, Kolbasova, EV, Kazakova, LV, Krasnov, VV, Shipova, LG, Lazareva, TS, Vlasova, IN, Schmaltz, AA (1998) The clinical picture and diagnosis of diphtheritic carditis in children. Eur JPediatr 157:528-33. 3. Perles, Z. Nir, A. Cohen, E, Basbary, A, Engelhard, D (2000) Atrioventricular Block in a Tox Child: Do Not Forget Diphtheria. Pediatr Cardiol 21:282-283.
NATIONAL HUMAN GENOME RESEARCH INSTITUTE National Institutes of Health Department of Health and Human Services MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AWARD WITH EMPHASIS ON THE APPLICATION OF GENOMIC OR PROTEOMIC TECHNOLOGIES (K23) The National Human Genome Research Institute is announcing a new career development award for clinicians who will engage in patient-oriented research that involves the application of the knowledge, tools, technologies and approaches of genomics and proteomics to the study of genetic diseases in an effort to develop effective therapeutic interventions. This award will provide support for three to five years of supervised study and research for clinically trained professionals who plan to become independent, productive clinical investigators focusing on patient-oriented research. The Mentored Patient-Oriented Research Career Development Award (K23) has several important features: (1) it requires an integrated clinical-laboratory research project that directly involves patients affected by the disease being studied so that awardees can develop skills in both clinical research and basic science, i.e. bench-to-bedside research; (2) it emphasizes career development and a research program that focuses on developing effective therapeutic interventions; projects that involve pre-therapeutic research will also be considered if the applicant can make a strong case that the knowledge gained from the study will provide a clear pathway toward the development of therapeutic interventions; and (3) it requires significant utilization of genomic and proteomic tools and technologies in the research project. The National Institute of Drug Abuse and the NIH Office of Rare Diseases are co-sponsors of this career development program. For additional information about this program, please visit this website: http://grants.nih.gov/grants/ guide/rfa-files/RFA-HG-03-006.html APPLICATION RECEIPT DATES: October 20, 2003; October 20, 2004; and October 20, 2005. PROGRAM CONTACT: Bettie J. Graham, Ph.D.; e-mail:
[email protected] The NHGRI's Division of Intramural Research has a companion program, Physician Scientist Development Program. The goal of this program is to train investigators who will be competitive for faculty positions at the NHGRI, other NIH institutes, or other top medical research institutions. The Division of Intramural Research is located in Bethesda, MD. For additional information about this program, please visit this website: http://www.genome.gov/page.cfm?pageID= 10002060. The NIH and DHHS are Equal Opportunity Employers.
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