Fatal Adenovirus Pneumonia in a Young Adult Associated with ADV-7 Vaccine Administered 15 Days Earlier

of bifascicular block secondary to penetrating cardiac injury. Bifascicu1ar block in this patient presumably reflected direct damage from the bullet impinging upon the summit of the ventricular septum. It is likely that the conduction system was damaged just distal to the "pseudobifurcation" of the His bundle, after the left posterior division had been given off. His bundle recordings suggested absence of damage to the left posterior division, in that H-V and RB-V intervals were normal and since no conduction defects distal to H were noted with atrial pacing. A-H prolongation probably reflected congenital first degree A-V block at the A-V node, a common abnormality of conduction. IS The congenital etiology is suggested by the presence of first degree A-V block noted on the patient's electrocardiogram prior to penetrating trauma.

Clinical Implications The patient has been followed in our conduction

disease clinic for the past year without change in the nature of his conduction defect. Electrophysiologic studies suggest that he is not at high risk for subsequent progression of conduction disease.

REFERENCES 1 Sustaita H, BaIsara RK, Niguidula FN, et al l Penetrating wounds of the heart. Chest 57 :340-343, 1970 2 Rosen KM, Heller R, Ehsani A, et all Localization of site of traumatic heart block with His bundle recordings. Am J Cardiol 30 :412, 1972 3 Lea CE : Shell wound of the heart causing complete heart block. Lancet 1:493, 1917 4 Armand P, Padridge R, Morel M, et all Syndrome d'Adams Stokes per blocJc A-V consecutif a une plaie thoracique paraballe. Arch Mal Coeur 51 :1187,1958 5 Naclerio EA: Penetrating wounds of the heart. Chest 46:1 ,1964 6 Sims BA, Seddes JS: Traumatic heart block. Br Heart J 31:140, 142, 1969 7 Rosenbaum MV, Elizari MV, Lazzari JO: The bemibloclcs. Oldsmar, Fla, Tampa Tracings, 1970 8 Damato AN, Lau SH, Berkowitz WD, et all Recording of specialized conducting Bbers (A-V nodal His bundle and right-bundle-branch) in man using an electrode catheter technique. Circulation 39:430-447, 1969 9 Rosen KM, Rahimtoola SH, Chuquimia R, et all Electrophysiological significance of first degree atrioventricular blodc with intraventricular conduction disturbances. Circulation 43:491-502, 1971 10 Dbingra R, Rosen KM, Rahimtoola SH: Normal conduction intervals and responses in 61 patients using His bundle recordings and atrial pacing . Chest 64 :55-59, U11'3 11 Rosen KM, Rahimtoola SH, Sinno Z, et al l Bundle branch and ventricular activation in man. A study using catheter recordings of left and right bundle branch potentials. Circulation 43:193-203, 1971 12 Narula OS, Chen LS, Samet P, et all Localization of A-V conduction defects in man by recording of the His bundle electrogram. Am J Cardiol25:228-235, 1970 13 Dolara A, PlYLZi L: Atrioventricular and intraventricular conduction defects after nonpenetrating trauma. Am Heart ]72:138-139 , 1966 14 Rosenbaum MB, Corrado S, Oliveri R, et all Right bundle branch block with left anterior hemiblock surgically in-

CHEST, 66: 2, AUGUST, 1974

15 16 17 18

duced in tetralogy of Fallot. Am J Cardiol 26:12-19, 1970 Rosen KM, Mehta A, Rahimtoola SH, et al l The sites of congenital and surgical heart block as defined by His bundle electrocardiography. Circulation 44:833, 1971 Parmley LF, Manion WC, Mattingly TW: Nonpenetrating injury of the heart. Circulation 18:371-396, 1958 Gozo EG, Cohen HC, Dick A: Traumatic blfascicular intraventricular block. Chest 61:294, 1972 Hiss RG, Averill KH, Lamb LE: Electrocardiographic findings in 67,375 asymptomatic individuals. In the First International Symposium on Cardiology in Aviation (pt 3) (Lamb LE, ed) USAF, Aerospace Medical Center, Brooks Air Force Base, Tesas, p 289

Fatal Adenovirus Pneumonia in a Young Adult Associated with ADV-7 Vaccine Administered 15 Days Earlier· E. F. Loke«, Ir., M.D., G. R. Hodges, M.D., and D. M.D.

J. KeUI/,

A 19-year-old man presented with mild respintory dis-

tress and bUatel1ll Intentltial iDftItndes on chest roent· genogram, ProgressIve, nltlmately fatal, respintory faDure eusued. AItbouP be bad received adenovirus (ADV) 4 and 7 01111 vacdne, the etiology w. most Ukely ADV-7, To our knowledge, this is the fint reported case of fu1minant ADV-7 pneumonitis assoclated with prior admin· Istration of ADV-7 vaccine.

A

cute respiratory tract disease (ARD), which is frequently seen in military recruits and primarily caused by adenovirus (ADV) types 4 and 7, may be an incapacitating but rarely a life threatening illness.I - 3 The frequency of ARD caused by these two viruses has been significantly reduced by the use of a live, oral, attenuated vaecine.>" Fatal AnV pneumonia occurs primarily in pediatric patients;9-12 however, recently the same entity has been recognized in adults undergoing military training. I , 1 3 A patient is presented who developed fulminant pneumonia caused by ADV-7 in spite of prior vaccination.

CASE REPoRT A 19-year-old man was admitted to the Naval Hospital, Great Lakes, Dlinois, on January 18, 1973, because of respiratory distress and mental confusion . The patient was in good health on arrival at Great Lakes on January 3, 1973, and the next day received live, oral, attenuated ADV 4 and 7 vaccine with the rest of his company, During the next 12 days, he was seen at sick-call on three occasions with fever and mild respiratory tract complaints which responded to symptomatic -From the Department of Medicine (Drs . Loker and Hodges) and the Laboratory Service (Dr. Kelly), Naval Hospital, Great Lakes, Illinois. The opinions and assertions contained herein are those of the authors and are not to be construed as official or as reBecting the views of the Navy Department or the Naval Service at large . Reprint requests: Dr. Hodges, Naval Regional Medical Center,

Great Lakes, Illinois 60088

FATAL ADENOVIRUS PNEUMONIA 197

treatment. However, when seen on January 15, 1973, he was symptomatic with fever, malaise, and dyspnea. Examination of the chest revealed scattered rales and rhonchi at both lung bases. Because a chest roentgenogram revealed bilateral interstitial infiltrates, he was admitted to the local dispensary and treated supportively. At the time of transfer to the Naval Hospital three days later, the patient was tachypneic and disoriented. Physical examination revealed: temperature 104" F, pulse 110, respirations 35 per minute, and blood pressure 140/100 mm Hg. The pharynx was injected without exudate. On auscultation of the chest there were rales, rhonchi, and decreased breath sounds at the right base and scattered rales at the left base posteriorly. Laboratory data on admission included: 3,800 white blood cells with 84 percent neutrophils, 13 percent lymphocytes, and 3 percent monocytes; serum bicarbonate, 19.6 mEq per liter; sodium, 114 mEq per liter; chloride, 70 mEq per liter ; potassium, 3.5 mEq per liter; serum osmolality, 234 mOsm per liter; urine osmolality, 289 mOsm per liter; urine sodium, 16 mEq per liter; and urine potassium, 17 mEq per liter . Arterial blood gases on room air were as follows: Pa02, 46.6 rom Hg; PaC02, 22.1 rom Hg; pH 7.45; and oxygen saturation, 83 percent. Chest roentgenogram revealed patchy right lower, right middle, and left lower lobe infiltrates (Fig 1). Admission impression was viral pneumonia with electrolyte and acid-base abnormalities. Initial therapy consisted of fluid and electrolyte replacement in addition to respiratory support. During the first three days of hospitalization the Pa02 was maintained between 60 and 70 mm Hg with 30 percent oxygen via mask and serum electrolytes returned to normal. On the fourth hospital day the patient's respiratory status deteriorated and adequate oxygenation could not be maintained with 100 percent oxygen via mask. Consequently, the patient was intubated and placed on a volume respirator. Tracheostomy was necessary within several hours of intubation because of difficulty in suctioning secretions through the endotracheal tube. At this time, coagulation studies revealed:

FIGURE 2. Section of postmortem lung showing alveolar septal thickening and fragmentation, intra-alveolar transudates with hyaline membrane formation, and focal alveolar cell hyperplasia (hematoxylin and eosin, original magnification X 128).

prothrombin time of 20.1 seconds (control, 11.8 seconds), partial thromboplastin time 58 seconds (control, 37 seconds), and platelet count of 57,000 per mm 3 • The patient had a lowgrade upper gastrointestinal hemorrhage, oozing from the tracheostomy site, and ecchymoses on the left arm. Intravenous infusion of heparin and fresh frozen plasma resulted in stabilization of the hematocrit at 30 percent and no further bleeding complications occurred. The patient's respiratory failure continued to deteriomte over the next five days despite the use of diuretics, fluid restriction, and a volume respirator with 100 percent oxygen and positive end-expiratory pressures between 10 and 18 em H20. On the tenth hospital day the patient had a cardiac arrest after which he could not be resuscitated. Arterial oxygen levels the day of death ranged from 35 to 45 rom Hg . Autopsy revealed striking gross and microscopic abnormalities involving the respiratory system. The lungs weighed 2070 gm and were diffusely noncrepitant. Alveolar septae were thickened and edematous. Abundant homogeneous to granular eosinophilic material filled nearly all alveoli and dense refractile intra-alveolar hyaline membranes were commonly noted (Fig 2) . Focal parenchymal destruction and hemorrhage without inflammatory response was prominant. Additional findings included denudation of bronchial and bronchiolar epithelium, focal alveolar cell hyperplasia with both giant cell and smudge cell formation, squamous metaplasia of the tracheal epithelium, minimal subepithelial and periglandular round-cell infiltrates in the tracheobronchial tree. No intravascular thrombi or intranuclear inclusions were noted in any of the tissue sections of all organs examined. Multiple cultures of blood, sputum, throat secretions, and urine throughout the clinical course as well as postmortem lung cultures were negative for bacteria, fungi, and mycobacteria with the use of routine methods. Cultures of HeLa, WI-38, and primary monkey kidney cells were inoculated with samples of antemortem stool, throat secretions, and tracheal secretions. ADV-7 was recovered from each of these samples; no other viruses were isolated. Postmortem tissue for viral isolation was not available. Results of viral serologic studies are shown in Table 1. DISCUSSION

1. Chest roentgenogram showing bilateral patchy infiltrates at time of hospital admission .

FIGURE

198 LOKER, HODGES, KELLY

The majority of cases of fatal ADV pneumonia have been reported in the pediatric age group;9-12 however, fatal cases among adults were noted recently. I. IS

CHEST, 66: 2, AUGUST, 1974

Table l-Yiral SeroloFe StatUe. Virus Adenovirus Pooled" Adenovirust Type 3 Type 4 Type 7

Hospital Day 5 9

128··

128

32

16 <4

<4

32

64

Influenza· Type A TypeB

256 16

256 16

Rhinovirust TypeIA TypeIB Type 2

16 <4 <4

<4 16

8

·By complement fixation. ··Expressed as reciprocal of titer. tBy neutralization.

Dudding and colleagues- in 1972 presented three cases whose clinical courses resembled that seen in our patient. Similarities include rapidly deteriorating respiratory failure, absolute lymphopenia, and disseminated intravascular coagulation. The present case differs in that live attenuated ADV 4 and 7 vaccine was received prior to the illness. The enteric coated ADV 4 and 7 vaccine causes selective, usually asymptomatic, gastrointestinal infeetion ., ,5 Fecal shedding of ADV is usual after immunization; nasopharyngeal shedding is unusual." The development of significant neutralizing antibody titers occurs in 95 percent of vaccinated individuals by the 21st day.s Although the protection afforded by ADV 4 and 7 vaccine is well documented.s" no appreciable decrease in ARD related hospitalizations occurs until three weeks after vaccination." The diagnosis of ADV-7 pneumonia in our patient is based on (1) isolation of only ADV-7 from tissue cultures inoculated with samples of stool, throat secretions, and tracheal aspirates and (2) the absence of bacterial, mycobacterial, or fungal agents in samples of blood, urine, sputum, and throat secretions obtained antemortem and lung tissue obtained postmortem. However, a four-fold rise in rhinovirus type 2 neutralizing antibody titer suggests the possibility of simultaneous infection with this virus, although this virus was not obtained on culture. The findings at autopsy were those of a viral pneumonia with negligible inflammatory response, denudation of bronchial epithelium, hyperplasia of the alveolar lining cells, and smudge and giant cell formation. 10 •1 2 Hyaline membranes, possibly secondary to oxygen therapy, were prominent as previously noted.' The data suggest two possible explanations for the development of ADV-7 infection in our patient. Either the infection was due to wild-type ADV-7 prior to the development of adequate vaccine-induced protection or the infection was caused by vaccine strain ADV-7. Because, to our knowledge, there is no generally accepted and reliable method of distinguishing wild-type from vaccine strain ADV-7, differentiation of these possibili-

CHEST, 66: 2, AUGUST, 1974

ties will require the development of such a test with subsequent careful epidemiologic, clinical, and laboratory study of ADV-7 disease in recently vaccinated individuals. ACKNOWLEDGMENT: The assistance of Drs. Dennis HoofHer and M. J. Rosenbaum in obtaining the viral studies, performed at Naval Medical Research Unit No; 4, Great Lakes, Dlinois, is greatly appreciated.

REFERENCES 1 Dudding BA, Wagner SC, Zeller JA, et all Fatal pneumonia associated with adenovirus type 7 in three military trainees. N Eng J Med 286:1289--1292, 1972 2 Top FH, Dudding BA, Russell PK, et al : Control of respiratory disease in recruits with types 4 and 7 adenovirus vaccines. Am J Epidem 94:142-146,1971 3 Rose HM, Lamson TH, Buescher EL: Adenovirus infection in military recruits . Arch Environ Health 21 :356-361, 1970 4 Couch RD, Chanock RM, Cate TR, et al: Immunization with types 4 and 7 adenovirus by selective infection of the intestinal tract. Am Rev Resp Dis 88 :394-403, 1963 5 Top FH, Grossman RA, Bartelloni PJ, et al l Immunization with live types 7 and 4 adenovirus vaccines I. Safety, infectivity, and potency of adenovirus type 7 vaccine in humans . J Infect Dis 124:148-154, 1971 6 Top FH, Buescher EL, Bancroft WH, et al: Immunization with live types 7 and 4. adenovirus vaccines II. Antibody response and protective effect against acute respiratory disease due to adenovirus type 7. J Infect Dis 124:155-160, 1971 7 Pierce WE, Rosenbaum MJ, Edwards EA, et all Live and inactivated adenovirus vaccine for the prevention of acute respiratory illness in naval recruits. Am J Epidem 87:237-

246,1968

8 Griffin JP, Greenberg BH: Live and inactivated adenovirus vaccines. Arch Intern Med 125:981-986, 1970 9 Steen-Johnson J, Orstavilc I, Attramadal A: Severe illness due to adenovirus type 7 in children. Acta Pediat Scand 58:157-163,1969 10 Benyesh-Melnick M, Rosenberg HS : The isolation of adenovirus type 7 from a fatal case of pneumonia and disseminated disease. J Pediat 64 :83-87,1964 11 Nahmias AJ, Griffith D, Snitzer J: Fatal pneumonia associated with adenovirus type 7. Am J Dis Child 114: 36-41,1967 12 Brown RS, Nogrady BM, Spence L, et all An outbreak of adenovirus type 7 infection in children in Montreal . Canad Med Assoc J 108:434-439, 1973 13 Levin S, Dietrich J, Guillory J: Fatal nonbacterial pneumonia associated with adenovirus type 4: Occurrence in an adult. JAMA 201:975-977,1967

Spherical Pneumonia * Phillip Stelne1', M.D., F.C.C.P.·· and Madu &0, M.D.t

A case of pneumonia oc:coning In a nine and one-halfyear-old boy is presented In which the lnitial x-ray film ·From The Department of Pediatrics, State University of New York, Downstate Medical Center, Brooklyn, N.Y. ••Assistant Professor of Pediatrics, State University of New York, Downstate Medical Center. tAssistant Clinical Professor of Pediatrics, State University of New York, Downstate Medical Center. Reprint r~quests: Dr. Steiner, Pediatrics, 450 Clarkaon Avenue, Brooklyn 11203

SPHERICAl PNEUMONIA 199