Benzonatate

Three cases of pertussis (whooping cough) identified in a military emergency department are reported. Two of these cases involved infants with typical presentations. One of these infants was too young to have received immunizations, and the other child was only partially immunized. The third case involved an active duty soldier with a chronic cough. Pertussis has become increasingly important as a cause of chronic cough in adults. As a result of the infectivity of this organism, close-quarter situations, such as day care centers and military barracks, create the opportunity for substantial person-to-- person transmission. Typical and atypical clinical presentations of pertussis are discussed, with an emphasis on currently available diagnostic modalities. The epidemiology and pathophysiology of this disease are also reviewed. The medical management of active duty soldiers and their dependents (both pediatric and adult) with this largely underappreciated infection and their close contacts is presented.

Introduction

Pertussis (whooping cough) is encountered infrequently in military medical practice. Despite agressive immunization programs, this disease continues to bea significant source of pediatric morbidity and mortality around the world. Pertussis remains largely underdiagnosed, especially in the United States. To prevent close contacts from developing clinical disease, physicians must maintain a high level of suspicion when evaluating and treating children and adults with upper respiratory infections. A case series of pertussis identified in two military beneficiary children, one with partial immunization and the other too young for initial immunization, is presented. A third case in an active duty soldier presenting with a persistent cough is also presented. These cases demonstrate the wide spectrum of clinical symptoms in pertussis infection and the favorable outcome when this disease is detected early and treated properly.

Case Series

Case 1

The patient was a 10-month-old male who presented to the emergency department (ED) with a chief complaint of wheezing, worsening cough, and "breath holding and turning blue." The family reported a history of 1 week of cough, congestion, and coryza. The patient was acting and feeding normally, with no fever, vomiting, diarrhea, or skin rash. During the preceding 8 to 12 hours, the patient had experienced numerous coughing spells, after which he would "hold his breath" and develop bluish skin. The mother was also ill with an upper respiratory infection.

The past medical history was significant for infection with respiratory syncytial virus at 3 weeks of age. The patient was taking no medications and had no known food or drug allergies. He last received immunizations at age 4 months, as a result of recurrent "colds." There was a family history of mild reactive airway disease in the mother.

On examination, the patient was nontoxic, interactive, and playful. The rectal temperature was 38.2 deg C (100.7 deg F), heart rate was 154 beats per minute (bpm), and respiratory rate was 40 breaths per minute. The oxygen saturation was 98% on room air. Capillary refill was normal. There was neither nasal flaring nor retractions or abdominal breathing. No stridor was present at rest. The lungs demonstrated diffuse expiratory wheezes.

A chest radiograph demonstrated mild peribronchial cuffing and air trapping. There was no infiltrate, effusion, or pneumothorax. No "steeple sign" was present. The white blood cell count was 17,300, with 32.7% neutrophils and 61.5% lymphocytes.

During his evaluation in the ED, the patient had three coughing spells, each lasting approximately 30 seconds. During these spells, the oxygen saturation decreased to 86% and the patient's lips and tongue became dusky blue. After each episode, the patient inhaled with an audible "whoop."

The patient was admitted to the pediatric ward in isolation. He was treated presumptively for pertussis with oral erythromycin. Direct fluorescent antibody (DFA) testing of nasopharyngeal secretions was positive for Bordetella pertussis, a finding confirmed by culture. The patient improved clinically, with no further desaturation episodes and no evidence of dehydration, and was discharged after 36 hours.

Case 2

A 27-day-old male infant presented to the ED with persistent coughing. He had coughed severely enough at home to cause a "choking episode," during which his lips turned blue, followed by immediate resolution. Post-tussive emesis was present. There was no associated fever, coryza, or congestion. The patient was a product of a full-term, uncomplicated pregnancy. The patients mother had a cough as well. Physical examination demonstrated a nontoxic infant. The rectal temperature was 37.0 deg C, heart rate was 120 bpm, and respiratory rate was 40 breaths per minute. There were no intercostal or supraclavicular retractions. The remainder of the physical examination was normal; a chest radiograph was also normal. One coughing episode was witnessed in the ED; there was no cyanosis or prolonged respiratory distress. Nasal washings for B. pertussis were obtained, and the child was discharged home with instructions for vigorous nasal saline irrigation.

Two days later, the child presented to our hospital's pediatric clinic for evaluation of persistent coughing, poor feeding, and lethargy. The infant appeared acutely ill; antibiotic therapy with cefuroxime and ampicillin was initiated, and a lumbar puncture was performed. The cerebrospinal fluid demonstrated normal protein, glucose, and white blood cell count. The peripheral white blood cell count was 23,300, with 72.3% lymphocytes.

The infant was admitted to a pediatric intensive care unit with the presumptive diagnosis of pertussis. DFA testing and culture of the nasal washings obtained on the prior visit confirmed B. pertussis. The child was treated with erythromycin, improved symptomatically, and was discharged 5 days later with no apparent untoward outcome.

Case 3

A 19-year-old female Advanced Individual Training student presented to the ED with a chief complaint of fever and coughing for 5 days. She had been seen in the troop medical clinic twice during the preceding week; she was diagnosed with an upper respiratory infection and started on amoxicillin therapy. She denied headache, sore throat, neck stiffness, urinary symptoms, and recent travel. She was a nonsmoker and had been exposed to multiple individuals with similar symptoms in an open-bay barracks.

The patient had no significant past medical or surgical history, and she was taking acetaminophen, fluticasone nasal inhaler, ibuprofen, and benzonatate in addition to amoxicillin. Her immunizations were up to date.

The patient was conversant and in no acute distress. Blood pressure was 122/62 mm Hg, pulse was 100 bpm, respiratory rate was 18 breaths per minute, temperature was 38.0 deg C, and oxygen saturation was 98%. Her oropharynx was unremarkable. The respiratory examination was notable only for referred upper airway sounds. The remainder of the physical examination was unremarkable. A chest radiograph demonstrated no infiltrate, effusion, pneumothorax, or peribronchial cuffing.

The patient had numerous coughing spells in the ED, prompting the treating physician to suspect pertussis. Nasal washings were obtained, and the patient was discharged to duty on oral erythromycin therapy. Both DFA testing and culture of the secretions were positive for B. pertussis.

Discussion

Pertussis continues to be an important clinical entity. First described in 1640,1 this disease was a leading cause of death in the infant population until the development of an effective vaccine in the 1930s and 1940s.2 The incidence of pertussis in the United States has decreased more than 100-fold since the introduction of vaccination; however, the disease remains endemic, with 6,755 cases reported in 2000.3 There remains a sizable population in the United States with decreased immunity as a result of poor implementation of vaccination programs, immigration from third world countries, and poor compliance. Throughout the world, pertussis continues to be a leading cause of death, responsible for 350,000 fatalities annually.4

The disease is extremely contagious, with transmission occurring via respiratory contact with aerosolized bacteria. Up to 100% of exposed nonimmune individuals will acquire the disease. In one study of household contact with pertussis cases in Germany, 179 of 263 children (68%) and 84 of 265 adults (32%) developed pertussis.5 Although humans are the only known hosts of B. pertussis, vaccination programs have not eliminated the circulation of the pathogen.6,7 Pertussis is particularly problematic in the close-quarters settings of military training and operations, and exposures in these settings should be considered as household contacts.

Clinical disease occurs when B. pertussis, a Gram-negative pleomorph, attaches to respiratory cilia. Elaboration of proteins and attachment factors from the bacteria contributes to the pathogenesis of disease. Pertussis toxin is a secreted endotoxin that has been demonstrated to be toxic to cells in tissue culture; however, the cellular effects of the toxin in vivo have not yet been fully described. Pertussis toxin may also have effects systemically, inhibiting chemotaxis of inflammatory cells and prolonging the course of disease.1,5 Adenylate cyclase toxin induces supraphysiological levels of cyclic adenosine monophosphate in host cells, resulting in decreased function of the cells of the immune system8 and apoptosis of macrophages.9 Filamentous hemagglutinin, periactin, and fimbriae are attachment factors that promote interaction, attachment, and entry of bacteria into host cells. The exact sequence of events during attachment has not been elucidated.10 Cilia are destroyed or rendered dysfunctional, partially by the effects of tracheal cytotoxin,10,11 with resultant failure to clear secretions, cellular debris, and foreign material. Thick secretions result, with development of coughing, bronchiectasis, and the clinical syndrome of pertussis.

Arriving at a diagnosis of pertussis is straightforward when patients present classically, as in case 1. After an incubation period of 7 to 10 days, patients develop protracted symptoms such as congestion, coryza, and low-grade fever. This stage, known as the "catarrhal" stage, lasts for 10 to 14 days. The onset of the "paroxysmal" stage is heralded by the development of a dry cough, progressing to the characteristic paroxysms of coughing that are the hallmark of the disease. A normal-appearing child will cough explosively and appear to choke. Associated cyanosis may or may not be present. After the coughing paroxysm, a forceful inspiratory gasp results in the audible "whoop" as air moves through the partially closed airway. Post-tussive emesis and exhaustion are common. Stigmata of increased intrathoracic pressure, such as subconjunctival hemorrhage, epistaxis, and punctate intraparenchymal hemorrhage, are also observed.

The paroxysmal stage fades after 10 to 21 days. Affected patients enter the "convalescent" stage, which may last several weeks. During this phase, the number and frequency of coughing spells will diminish, although paradoxically the "whoop" may become louder.12,13

Diagnosis is more challenging with atypical presentations, such as our case 2. Classic symptoms, coughing, and whooping are frequently absent in infants and partially immunized children. Older children and adults may also become infected, displaying only symptoms of upper respiratory infection or a persistent cough. without the classic stages of pertussis, as demonstrated in our third case. Many adults may have asymptomatic infections, and it is believed that these adults serve as reservoirs of the disease. 14 The diagnosis must be suspected in any patient presenting with a complaint of cough, especially of 2 weeks duration or greater. Infants of mothers younger than 19 years and infants whose mothers had a cough history of 7 days or greater have a higher incidence of Bordetella infection.15 Partially or fully immunized children and adults are still at risk for development of the disease, although often of shorter duration and lesser severity than in the unimmunized population.6

Adjunctive studies may also aid in the diagnosis. Absolute lymphocytosis (20,000-40,000 cells/mm^sup 3^) is often present during the first two stages in children. Chest radiographs may demonstrate nonspecific findings of peribronchial cuffing and air trapping. Blood cultures are usually negative. Serological studies have a wide range of sensitivity (25-100%) and specificity (15-100%)1 under ideal conditions, making their usefulness questionable. The specificity decreases when multiple antibodies (immunoglobulin [IgI A, IgG, and IgM for pertussis toxin, filamentous hemagglutinin, periactin, fimbriae, and agglutinogens) are tested.16 DFA studies, using nasopharyngeal mucus, are now used by many institutions. DFA has the advantage of a high specificity with trained microscopists and the appropriate reagents,17 but it has the disadvantage of a low sensitivity.18 The "gold standard" is culture of B. pertussis; however, growth often takes days, yielding results too late for clinical utility. The cultures require specialized media, such as the medium described by Regan and Lowe,19 to preferentially grow the organism and to eliminate other respiratory bacteria. The sensitivity of culture as a diagnostic gold standard is also questionable because of the high rate of false-negative results.18 In obtaining a nasopharyngeal sample for culture, an aspiration is preferable to swabs. Dacron swabs are more useful than cotton, which may be toxic to the organism, or alginate, which may inhibit assays that use the polymerase chain reaction (PCR).18 PCR may provide an excellent modality for diagnosis as techniques are refined and applicability in a clinical setting is validated.187,20,21 However, PCR has not been advocated for standard clinical practice. Laboratories may encounter difficulties with contamination, which could yield false-positive results.

Studies of adults using serological testing have indicated a high prevalence of pertussis in adults presenting with chronic cough.10,22-27 These studies described patients with positive serological testing but negative cultures. Multiple antibodies were tested in each of these studies; therefore, it is possible that the incidence of pertussis may be overestimated as a result of deceased specificity.16 Additional studies on different adult populations have indicated a high prevalence of pertussis antibodies in adults who do not report a significant illness.28 A study of active duty soldiers in Korea with chronic cough noted that 4 (7%) of 54 patients demonstrated serological evidence of pertussis infection.29 Underreporting of the disease to the Centers for Disease Control and Prevention is believed to be substantial, with preferential reporting of cases associated with severe complications.30

Although most treatment of pertussis is supportive and managed on an outpatient basis, complications may develop that require hospitalization. The physician must anticipate these complications when determining patient disposition. Complications of pertussis include apnea, secondary infections, effects of forceful coughing, and dehydration. Seizures and encephalopathy rarely occur. These complications are likely caused by hypoxia and cephalic microhemorrhages that occur during prolonged coughing paroxysms. Infants younger than 3 months of age are at highest risk for severe complications. Several paroxysms should be witnessed in the ED before deciding on disposition. If paroxysms lead to desaturation, cyanosis, post-tussive unresponsiveness, or inability to feed, admission is indicated. Infants younger than 3 months of age, prematurely born infants, those with significant comorbidities, and those with nonsupportive family situations should also be admitted regardless of their appearance in the ED. Hospitalized children require respiratory isolation and monitoring of paroxysms, with airway assistance to include supplemental humidified oxygen, as well as suctioning or endotracheal intubation if needed. As a result of poor feeding, infants are frequently dehydrated and require intravenous fluid resuscitation as well. Central nervous system manifestations and secondary infection should be managed accordingly. The most common causes of death are secondary pneumonia and the respiratory distress syndrome.

The cornerstone of therapy is antibiotics. Erythromycin estolate, 40 to 50 mg/kg/d divided q.i.d., is the treatment of choice for both the affected patient and for close contacts, regardless of symptomology, to prevent transmission. Erythromycin resistance is uncommon but has been reported.31 Trimethoprimsulfamethoxazole is the second-line agent, given at a dosage of 5 mg/kg (trimethoprim) divided b.i.d. Both regimens should be administered for a total of 14 days. Newer macrolide antibiotics have been demonstrated to be effective in vitro, but currently there are little data describing their efficacy in vivo.32,33 However, the use of antibiotics has not been shown to alter the clinical course of disease unless given during the incubation period, early in the catarrhal phase, or in the presence of secondary bacterial infection. Antibiotic use, however, may decrease transmission of the agent to other individuals. There has been no proven benefit from inhaled beta-agonists or corticosteroids.12

Children who have been diagnosed with pertussis should refrain from day care or school attendance until 5 full days of antibiotic therapy have been completed. Children who have been exposed should be observed for 2 weeks. If respiratory symptoms develop, these children should be excluded from day care or school until evaluated by a physician.7 Health care workers exposed to pertussis should be treated with erythromycin as chemoprophylaxis for 14 days and wear a mask whenever caring for children younger than 4 years until 5 days of antibiotics have been completed.14,34 Household contacts should also be considered for chemoprophylaxis as well. Commanders should consider isolating soldiers for a similar period, particularly those living in open-bay barracks; unit surgeons should consider administering prophylactic antibiotics to soldiers exposed to affected patients. Preventive medicine staff can provide assistance to the physician confronting the often difficult decision about personnel who should receive prophylaxis.

Conclusion

Military physicians may play a key role in preventing significant morbidity and mortality as well as preventing transmission of this highly contagious yet easily treated disease. This disease is highly contagious and appears to have a significant prevalence in adolescents and young adults. Military physicians need to be aware of the various clinical presentations and treatment considerations associated with pertussis. Maintaining a high clinical suspicion, aggressive management of the disease and its complications, treatment of close personal contacts, and proper reporting of suspected or proven cases to public health authorities ought to yield satisfying outcomes for patients, families, and the physician.

Acknowledgments

The authors thank COL David Dooley, LTC Robert DeLorenzo, MAJ Kelly Abbrescia, MAJ Robert Gerhardt, and Maj Craig Manifold for manuscript review.

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Guarantor: MAJ Frank L. Christopher, MC FS USA

Contributors: MAJ Frank L. Christopher, MC FS USA*^; CnP) Matthew J. Hepburn, MC USA^^; MAJ Robert A. Frolichstein, MC USA^

*San Antonio Uniformed Services Health Education Consortium Emergency Medicine Residency, ^Department of Emergency Medicine, and ^^Department of Infectious Diseases, Brooke Army Medical Center, Fort Sam Houston, TX 78234.

This manuscript was received for review in June 2001 and was accepted for publication in August 2001,

Reprint & Copyright (c) by Association of Military Surgeons of U.S., 2002.

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