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Virus croup
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o n C u r r e n t Literature VIRUS CROUP
NFECTIONS of the r e s p i r a t o r y constitute a m a j o r group among the illnesses of infants and children and, in the y o u n g child, croup can be a serious manifestation. The characteristic lesion is an inflammat o r y process involving the larynx, trachea, and bronchi. The g r a v i t y of the illness and the severity of the s y m p t o m s depend to a considerable extent u p o n the amount of edema of the vocal cords and the subglottic structures which accounts for' the narrowing of the a i r w a y and the subsequent r e s p i r a t o r y difilculty. Inflammation m a y extend also into the ]ower r e s p i r a t o r y tract. I n some instances stenosis oi the air passages m a y be a g g r a v a t e d by m e m b r a n e formation as is typical in diphtheritic croup. Res p i r a t o r y embarrassment is the most common cause of death. Conventional bacteriologic studies are often reported as negative, or m a y reveal a variety of organisms--streptococcus, staphylococcus, pneu~mcoecus, Hemophilus 4nfluenzae, et cetera. Rabe ~ was among the first to point out the possible viral etiology of infectious croup azad to. suggest that in some instances the bacterial agents recovered might not represent the prim a r y invasion. A s t u d y first reported in 1947 was p r o m p t e d by " t h e considerable difference of opinion as to
the: etiologic role of the various bact e r i a found in association with the disease."1 Rabe postulated t h a t the majority of eases of croup are essentially viral in origin. H e reached this conclusion on the basis of an extensive investigation of the bacteriologT, pathology, and clinical course of 347 cases of infectious croup, g r o u p i n g the patie~lts into " t h r e e etiologic categories; namely, diphtheritic croup, H. influenza.e t y p e B croup, a n d so-called ' v i r u s ' c r o u p . " Of the 347 cases, only about 14 per cent could be shown to be associated with bacterial pathogens. Rabe described the v i r u s t y p e of croup as distinct in its pathologic manifestations f r o m croup due to ti. influenzae type B, or to Corynebacterium diphtheriae, and as similar to viral influenza in the h u m a n subject and to laryngotracheitis in fowls. Clinically the disease appears to be progressive with a downward spread of the infection in the respiratory tract. Inflammation extending into various regions is expressed in such clinical forms of the disease as laryngitis, laryngotracheitis, or laryngotracheopneumonitis. Mortality increases as the disease spreads down the respiratory tract, and one of the most frequent severe complications of this t y p e of croup is the occurrence of extra-alveolar thoracic air.
I tract
793
794
THE
J O U R N A L OF P E D I A T R I C S
Developments within the past few years have brought these early observa.tions into new significance. The consistent failure of antibiotic agents to influence the clinical course in this type of infection has paralleled the lack o.f significant bacterial agents cultured during the acute illness in these patients. While virus isolation had been attempted in some instances, it was not until 1955 and 1956 that the croup-associated viruses began to be isolated and identified. In the fall and winter of 1955 a widely disseminated virM agent appeared to be associated with croup or, in older ehildren, with respiratory illnesses characterized by croupy cough, the Inanifestations depending to, a large extent upon the age of the patient. At this time Chanoek 2 reported the finding of a new strain of virus of the myxovirus type in eases of infantile croup. Somewhat later similar isolations were reported by Beale, Rhodes, and their associates, a and also. by Cramblett, 4 eytopathogenic agents of this same type being isolated from infants and young children w i t h laryngotraeheobronehitis. As the name implies, the myxoviruses are characterized by a special affinity for certMn mucins. 5 The virus section of t h e International Nomenclature Committee has provided a short description of this group which includes the agents of influenza A, B, and C, Newcastle disease, fowl plague, and mumps. These viruses are similar in size, and have a group-specific soluble antigen. They have the quality of adsorption to and subsequent agglutination of erythrocytes, in some instances with hemolysis; later the virus elutes leaving irreversible alterations in the mucoprotein receptors of
the red cell surface. The newly described hemadsorption viruses (IIA viruses) belong to. this myxovirus group; they are known to be associated with acute respiratory infections, pharyngitis, pneumonitis, and the like. Their isolation has been accomplished chiefly by means of the VogelShelako~ 6 technique which involves the use of monolayer monkey kidney tissue cultures to. which guinea pig erythroeytes adsorb readily in the presence of these so-called hemadsorption viruses. With certain modifications in the, technique these tissue culture preparations can be used for the detection of virus in material o t i s hating from throat swabs or from nasopharyngeM washings of patients showing acute respiratory disease. 7 Siguifieant studies of the hemadsorption vi~%tses and other croup-associated viruses are being reported currently by Chanock and his associates, s a group of investigators who have been interested in the "respiratory viruses" fo.r some. years. In October, 1957, two new myxoviruses, hemadso.rption viruses types I and 2, were isolated from the oropharyrL,~ of children. Subsequent investigations indiGated that these viruses are: of significance in respiratory-traet disease in children. The clinical findings in affected children included " a wide spectrum of respiratory-tract illness varying from rhinitis and bronchitis with or without fever through the relatively severe Group syndrome or broncho.pneumonia." The newly isolated strains of virus exhibited the property of hemadsorption, and were capable of hemagglutinating both fowl and guinea pig erythroeytes. These two hemadsorption viruses (types 1 and 2) showed certMn antigens in common
COMNiENTS ON CURRENT LITERATURE
with the other myxoviruses, but were found to be serologically distinct from each other and from other known human myxoviruses. An evaluation of the data oil 42 patients with infection due to type 1, and 50 patients with infection due to type 2 revealed considerable overlapping in the clinical manifestations, which included cough, rhinorrhea, and pharyngitis as major symptoms. More severely ill patients had respiratory distress or croupy c o u g h . , Pharyngeal erythema was a common physical sign, with the more severely ill patients showing dyspnea, abnoruml Hung findings such as rhonchi and r~les, or sig"ns of laryngeal obstruction. P a r t of the epidemiologic study 9 of the type 2 strain of hemadsorption virus included its transfer to human volunteers (adults), and an investigation of the range of severity of clinical manifestations in adults as compared with those in children. A recent report b y this group of investigators, ~~ appears in the New England Journal of Medicine for J u l y 2, 1959, and concerns the association of hemadsorption virus type 2 (parainfluenza 1) and Asian influenza virus A with infectious croup. A diag~nosis of virus infection could be assigned to 71 per cent of the children With croup. The associated viruses included influenza virus, hemadsorption virus types 1 and 2, croup-ass0eiated virus, and adenovirus types 1 and 5. In the study by these authors " t h e agents whose association with croup was best substantiated w e r e hemadsorption virus t y p e 2 and the virus of Asian influenza A . " As the authors point out, the association of influenza viruses with croup was long suspected and is
795
now- being documented. 1, 1 1 The association of the hemadsorption virus t y p e 2 with croup is a new observation, and according to the authors was the most striking finding in their investigations with the hemadsorption viruses. In all probability these new myxoviruses will be classified as Myxovirus parainfluenzae 3 (hemadsorption virus type 1) and Myxovirus parainfluenzae 1 (hemadsorption virus type 2 ) 2 2 Significant bacterial pathogens were not found to be associated with these respiratory illnesses. An interesting clinical observation was the notable differences in the manifestations of this type of virus croup from those considered characteristic of the socalled supraglottic form of croup resuiting from infection with H. influenzae type B. Another observation of interest concerned the predilection of type 2 hemadsorption virus for male children, a finding in accord with earlier notations that croup occurs less frequently in females. In a careful summary of the clinical and laboratory findings the authors state that if these studies " . . . are confirmed in the future, hemadsorption virus Typc~ 2 is probably one of the major causes of infectious croup and accounts for a large segment of previously unexplained illness. These observations, if substantiated, will make this agent a leading candidate for inelusion in any vaccine against respiratory tract viruses. ' ,lo RUSSELL J . BLATTNER REFERENCES 1. Rabe, E. I~.: Infectious Croup: I. Etiology, Pediatrics 2: 255, 1948; II. " V i r u s " Croup, Pediatrics 2: 415, 1948 ; III. tIemophilus Influenzae Type B Croup, Pediatrics 2: 559, 1948.
796
THE JOURNAL OF PEDIATRICS
2. Chanock, R. M. : Association of a l~ew Type of Cytop~thogeaic Myxavirus With Infantile Croup, J. E x p e l Med. 104: 5557 1956. 3. Beale, A. J., McLeod, D. L., Stacklw, W., and Rhodes, A. J.: Isolation of Cytopathogenic Agents From the Respiratory Tract in Acute Laryngotracheobronchitis , Brit. M. J. 1: 302, 1958. 4. Cramblett, It. G.: Isolation of Cytopathogenic Agent Resembling the CA Virus From an Infant With Croup, Pediatrics 22: 56, 1958. 5. Rhodes, A .J., and van Rooyen, C. E.: Virology for Students and Practitioners of Medicine, Baltimore, 1958, Williams & Wilkins Compauy, chap. 21. 6. Vogel, J. E., and Shelakov, A.: Adserp-
8.
9.
10.
tion-Hemagglutination T e st for Influenza Virus in 1V[onkey I(iduey Tissue
Cultur% Science 126: 358, 1957; She]akov, A., Vogel, J. E., and Chl, Lotto: Hemadsorption ( Adsorption-ttemagglutination) Test for Viral Agents iu Tissue Culture With Special Reference to Influenza, Proc. Soc. Exper. Biol. & Med. 97: 802, 1958. 7. Chanoek, R. M., Parrott, R. H., Cook, ]~atherine, Andrews, B. E., Bell, J. A.,
]]. 12.
Reichelderfer, Thos., Kapikian, A. Z., Mastro~a, F. M., and Huebner, R. J . : Newly Recognized Myxoviruses From Children With Respiratoi T Diseas% New England J. Med. 258: 207, 1958. Parrott, R. II., Vargesko, A. J., Lackey, A. tI., I~im, H. W., Caroming, C., and Chanock, R. M.: Clinical Features of Infection with tIemadsorptiou Viruses, New England J. Med. 260" 731, ]959. Reichelderfer, T. E., Chanock, R. M. I Craighead, J. E., ~uebner, R. J., Turner, tI. C, and James) Walter: Infection of IIuman Volunteers With Type 2 IIemadsorptiou Virus, Science 128: 779, 1958. Vargosko, A. J , Chanock, R. M.~ IIuebnor, R. J , Luckey, A. If., Him, H. W., Cumming, C., and Parrott, R. H . : Association of Type 2 I-Iemadsorption (Parainfluenza 1) Virus and Asian Influenza A Virus With Infectious' Croup, New England J. Pied. 261: 1~ 1959. Forbes, J . A . : Severe Effects of Influenza Virus Infection, M. J. Australia 2: 75, ]958. Andrewes, C. I-I., Bang, F. B., Chanoek, R. M., and Zhdanov, V. M. : Parainfluenza Virus i, 2, 3: Suggested Names for Recently Described Myxoviruses, Virolog3r 8: 129, ]959.
o n C u r r e n t Literature VIRUS CROUP
NFECTIONS of the r e s p i r a t o r y constitute a m a j o r group among the illnesses of infants and children and, in the y o u n g child, croup can be a serious manifestation. The characteristic lesion is an inflammat o r y process involving the larynx, trachea, and bronchi. The g r a v i t y of the illness and the severity of the s y m p t o m s depend to a considerable extent u p o n the amount of edema of the vocal cords and the subglottic structures which accounts for' the narrowing of the a i r w a y and the subsequent r e s p i r a t o r y difilculty. Inflammation m a y extend also into the ]ower r e s p i r a t o r y tract. I n some instances stenosis oi the air passages m a y be a g g r a v a t e d by m e m b r a n e formation as is typical in diphtheritic croup. Res p i r a t o r y embarrassment is the most common cause of death. Conventional bacteriologic studies are often reported as negative, or m a y reveal a variety of organisms--streptococcus, staphylococcus, pneu~mcoecus, Hemophilus 4nfluenzae, et cetera. Rabe ~ was among the first to point out the possible viral etiology of infectious croup azad to. suggest that in some instances the bacterial agents recovered might not represent the prim a r y invasion. A s t u d y first reported in 1947 was p r o m p t e d by " t h e considerable difference of opinion as to
the: etiologic role of the various bact e r i a found in association with the disease."1 Rabe postulated t h a t the majority of eases of croup are essentially viral in origin. H e reached this conclusion on the basis of an extensive investigation of the bacteriologT, pathology, and clinical course of 347 cases of infectious croup, g r o u p i n g the patie~lts into " t h r e e etiologic categories; namely, diphtheritic croup, H. influenza.e t y p e B croup, a n d so-called ' v i r u s ' c r o u p . " Of the 347 cases, only about 14 per cent could be shown to be associated with bacterial pathogens. Rabe described the v i r u s t y p e of croup as distinct in its pathologic manifestations f r o m croup due to ti. influenzae type B, or to Corynebacterium diphtheriae, and as similar to viral influenza in the h u m a n subject and to laryngotracheitis in fowls. Clinically the disease appears to be progressive with a downward spread of the infection in the respiratory tract. Inflammation extending into various regions is expressed in such clinical forms of the disease as laryngitis, laryngotracheitis, or laryngotracheopneumonitis. Mortality increases as the disease spreads down the respiratory tract, and one of the most frequent severe complications of this t y p e of croup is the occurrence of extra-alveolar thoracic air.
I tract
793
794
THE
J O U R N A L OF P E D I A T R I C S
Developments within the past few years have brought these early observa.tions into new significance. The consistent failure of antibiotic agents to influence the clinical course in this type of infection has paralleled the lack o.f significant bacterial agents cultured during the acute illness in these patients. While virus isolation had been attempted in some instances, it was not until 1955 and 1956 that the croup-associated viruses began to be isolated and identified. In the fall and winter of 1955 a widely disseminated virM agent appeared to be associated with croup or, in older ehildren, with respiratory illnesses characterized by croupy cough, the Inanifestations depending to, a large extent upon the age of the patient. At this time Chanoek 2 reported the finding of a new strain of virus of the myxovirus type in eases of infantile croup. Somewhat later similar isolations were reported by Beale, Rhodes, and their associates, a and also. by Cramblett, 4 eytopathogenic agents of this same type being isolated from infants and young children w i t h laryngotraeheobronehitis. As the name implies, the myxoviruses are characterized by a special affinity for certMn mucins. 5 The virus section of t h e International Nomenclature Committee has provided a short description of this group which includes the agents of influenza A, B, and C, Newcastle disease, fowl plague, and mumps. These viruses are similar in size, and have a group-specific soluble antigen. They have the quality of adsorption to and subsequent agglutination of erythrocytes, in some instances with hemolysis; later the virus elutes leaving irreversible alterations in the mucoprotein receptors of
the red cell surface. The newly described hemadsorption viruses (IIA viruses) belong to. this myxovirus group; they are known to be associated with acute respiratory infections, pharyngitis, pneumonitis, and the like. Their isolation has been accomplished chiefly by means of the VogelShelako~ 6 technique which involves the use of monolayer monkey kidney tissue cultures to. which guinea pig erythroeytes adsorb readily in the presence of these so-called hemadsorption viruses. With certain modifications in the, technique these tissue culture preparations can be used for the detection of virus in material o t i s hating from throat swabs or from nasopharyngeM washings of patients showing acute respiratory disease. 7 Siguifieant studies of the hemadsorption vi~%tses and other croup-associated viruses are being reported currently by Chanock and his associates, s a group of investigators who have been interested in the "respiratory viruses" fo.r some. years. In October, 1957, two new myxoviruses, hemadso.rption viruses types I and 2, were isolated from the oropharyrL,~ of children. Subsequent investigations indiGated that these viruses are: of significance in respiratory-traet disease in children. The clinical findings in affected children included " a wide spectrum of respiratory-tract illness varying from rhinitis and bronchitis with or without fever through the relatively severe Group syndrome or broncho.pneumonia." The newly isolated strains of virus exhibited the property of hemadsorption, and were capable of hemagglutinating both fowl and guinea pig erythroeytes. These two hemadsorption viruses (types 1 and 2) showed certMn antigens in common
COMNiENTS ON CURRENT LITERATURE
with the other myxoviruses, but were found to be serologically distinct from each other and from other known human myxoviruses. An evaluation of the data oil 42 patients with infection due to type 1, and 50 patients with infection due to type 2 revealed considerable overlapping in the clinical manifestations, which included cough, rhinorrhea, and pharyngitis as major symptoms. More severely ill patients had respiratory distress or croupy c o u g h . , Pharyngeal erythema was a common physical sign, with the more severely ill patients showing dyspnea, abnoruml Hung findings such as rhonchi and r~les, or sig"ns of laryngeal obstruction. P a r t of the epidemiologic study 9 of the type 2 strain of hemadsorption virus included its transfer to human volunteers (adults), and an investigation of the range of severity of clinical manifestations in adults as compared with those in children. A recent report b y this group of investigators, ~~ appears in the New England Journal of Medicine for J u l y 2, 1959, and concerns the association of hemadsorption virus type 2 (parainfluenza 1) and Asian influenza virus A with infectious croup. A diag~nosis of virus infection could be assigned to 71 per cent of the children With croup. The associated viruses included influenza virus, hemadsorption virus types 1 and 2, croup-ass0eiated virus, and adenovirus types 1 and 5. In the study by these authors " t h e agents whose association with croup was best substantiated w e r e hemadsorption virus t y p e 2 and the virus of Asian influenza A . " As the authors point out, the association of influenza viruses with croup was long suspected and is
795
now- being documented. 1, 1 1 The association of the hemadsorption virus t y p e 2 with croup is a new observation, and according to the authors was the most striking finding in their investigations with the hemadsorption viruses. In all probability these new myxoviruses will be classified as Myxovirus parainfluenzae 3 (hemadsorption virus type 1) and Myxovirus parainfluenzae 1 (hemadsorption virus type 2 ) 2 2 Significant bacterial pathogens were not found to be associated with these respiratory illnesses. An interesting clinical observation was the notable differences in the manifestations of this type of virus croup from those considered characteristic of the socalled supraglottic form of croup resuiting from infection with H. influenzae type B. Another observation of interest concerned the predilection of type 2 hemadsorption virus for male children, a finding in accord with earlier notations that croup occurs less frequently in females. In a careful summary of the clinical and laboratory findings the authors state that if these studies " . . . are confirmed in the future, hemadsorption virus Typc~ 2 is probably one of the major causes of infectious croup and accounts for a large segment of previously unexplained illness. These observations, if substantiated, will make this agent a leading candidate for inelusion in any vaccine against respiratory tract viruses. ' ,lo RUSSELL J . BLATTNER REFERENCES 1. Rabe, E. I~.: Infectious Croup: I. Etiology, Pediatrics 2: 255, 1948; II. " V i r u s " Croup, Pediatrics 2: 415, 1948 ; III. tIemophilus Influenzae Type B Croup, Pediatrics 2: 559, 1948.
796
THE JOURNAL OF PEDIATRICS
2. Chanock, R. M. : Association of a l~ew Type of Cytop~thogeaic Myxavirus With Infantile Croup, J. E x p e l Med. 104: 5557 1956. 3. Beale, A. J., McLeod, D. L., Stacklw, W., and Rhodes, A. J.: Isolation of Cytopathogenic Agents From the Respiratory Tract in Acute Laryngotracheobronchitis , Brit. M. J. 1: 302, 1958. 4. Cramblett, It. G.: Isolation of Cytopathogenic Agent Resembling the CA Virus From an Infant With Croup, Pediatrics 22: 56, 1958. 5. Rhodes, A .J., and van Rooyen, C. E.: Virology for Students and Practitioners of Medicine, Baltimore, 1958, Williams & Wilkins Compauy, chap. 21. 6. Vogel, J. E., and Shelakov, A.: Adserp-
8.
9.
10.
tion-Hemagglutination T e st for Influenza Virus in 1V[onkey I(iduey Tissue
Cultur% Science 126: 358, 1957; She]akov, A., Vogel, J. E., and Chl, Lotto: Hemadsorption ( Adsorption-ttemagglutination) Test for Viral Agents iu Tissue Culture With Special Reference to Influenza, Proc. Soc. Exper. Biol. & Med. 97: 802, 1958. 7. Chanoek, R. M., Parrott, R. H., Cook, ]~atherine, Andrews, B. E., Bell, J. A.,
]]. 12.
Reichelderfer, Thos., Kapikian, A. Z., Mastro~a, F. M., and Huebner, R. J . : Newly Recognized Myxoviruses From Children With Respiratoi T Diseas% New England J. Med. 258: 207, 1958. Parrott, R. II., Vargesko, A. J., Lackey, A. tI., I~im, H. W., Caroming, C., and Chanock, R. M.: Clinical Features of Infection with tIemadsorptiou Viruses, New England J. Med. 260" 731, ]959. Reichelderfer, T. E., Chanock, R. M. I Craighead, J. E., ~uebner, R. J., Turner, tI. C, and James) Walter: Infection of IIuman Volunteers With Type 2 IIemadsorptiou Virus, Science 128: 779, 1958. Vargosko, A. J , Chanock, R. M.~ IIuebnor, R. J , Luckey, A. If., Him, H. W., Cumming, C., and Parrott, R. H . : Association of Type 2 I-Iemadsorption (Parainfluenza 1) Virus and Asian Influenza A Virus With Infectious' Croup, New England J. Pied. 261: 1~ 1959. Forbes, J . A . : Severe Effects of Influenza Virus Infection, M. J. Australia 2: 75, ]958. Andrewes, C. I-I., Bang, F. B., Chanoek, R. M., and Zhdanov, V. M. : Parainfluenza Virus i, 2, 3: Suggested Names for Recently Described Myxoviruses, Virolog3r 8: 129, ]959.