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Exaggerated antibody response following rubella vaccination in a child with sinus histiocytosis with massive lymphadenopathy
Volume 89 Number I
to enteroviral infection is the case of a 3-year-old boy, from w h o m coxsackie A9 virus was recovered from swabbings of pharynx and rectum? This child showed sparing of the pupillomotor fibers, and involvement of the levator palpebrae and the four extraocular muscles innervated by the oculomotor nerve, similar to our patient. H e also recovered completely. The enteroviruses are neurotropic and may cause a variety of manifestations referable to all parts of the central and peripheral nervous systems. Coxsackie and E C H O viruses are c o m m o n causes of epidemic and sporadic lymphocytic meningitis, encephalitis associated with cranial nerve deficits including involvement of extraocular muscles2 ataxia, ~ a parkinsonian syndrome, ~ and acute ascending polyradieulomyelitis? W e would speculate that the site of viral i~(~ction in our patient was limited to the motor neurons~of the oculomotor nucleus. Acute unilateral oculomotor neuropathy with sparing of pupillomotor fibers is most likely due to a self-limited enteroviral infection. Invasive diagnostic procedures may safely be deferred if no other neurologic deficits develop.
Exaggerated antibody response following rubella vaccination in a child with sinus histiocytosis with massive lymphadenopathy Ciro V, Sumaya, M.D.,* San Antonio,
Brief clinical and laboratory observations
81
We thank Ms. Rose Rita Schlnidt, virology technician, for her assistance with the viral cultures and titer determinations. REFERENCES 1. Knox DC, Clark DB, and Schuster FF: Benign sixth nerve palsies in children, Pediatrics 40:560, 1970. 2. Saunders WH: Viral infections and cranial nerve paralysis, Arch Otolaryngol 78:101, 1963. 3. Nemet P, Ehrlich D, and Lazar M: Benign abducens palsy in varicella, Am J Ophthal 78:859, 1974. 4. Marzetti G, Midulla M, and Baldncci L: Paralisi monolaterale del III paio dei nervi craniei da virus Coxsackie A9, Minerva Pediatr 20:943, 1968. 5. Karzan DT: An epidemic of ~eptid meningitis syndrome due to ECHO virus type 6, Pediatrics 29:4i8, 1962. 6. Ravetto F, Ghidella G, and Colonna F: Acute benign ataxia referable to Coxsackie A. 5 cases observed during 1he summer of 1967, Minerva Pediatr 20:2227, 1968. 7. Waiters JH: Post-encephalitis parkmson syr~drome after meaingoencephalitis due to Coxsackie group 13, type 2, N Engl J Med 263:744, 1960. 8. Forbes SJ, Brumlik J, and Harding HB: Acute ascending polyradiculomyelitis associated with ECHO 9 virus, Dis Nerv Syst 28:537, 1970.
Table I. Serum antibody titers* to rubella virus following rubella immunization in a child with S H M L
Antibody titers Date of serum
6/71 7/71 9/71 10/71 8/72
Hemagglutinationinhibiting (HAI)~f 163,840 40,960 20,480 20,48~ 20,480
[ Neutralizing~ 80 160
*All titers are expressed as reciprocals of serum dilutions. ~Method of Stewart and associates4 with kaolin-treated serum. SPerformed by standard methods with 32 TCID~0of virus?
Texas, James D. Cherry, M.D., Los Angeles, Calif., and Robert Gohd, M.D., New Orleans, La. S I N u s I~I s T I o c,z x o s I s with massive lymphadenopathy is a recently described entity seen mainly in black chil-
From the Infectious Diseases Division, Department of Pediatrics, UCLA School of Medicine, and the Virology Laboratory, Charity Hospital at New Orleans. *Reprint address: Departmentof Pediatrics, The Universityof Texas Health Science Center at San Antonio, 7703Floyd Curl Drive, San Antonio, Texas 78284.
dren. 1 It is characterized by massive, painless, cervical lymphadenopathy, fever, hypergammaglobulinemia, and leukocytosis. The unique microscopic picture of the revolved lymph nodes features dilatation of the sinuses and numerous intrasinusal histiocytes containing phago-
Abbreviations used SHML: sinus hisliocytosis with massive iymphadenopathy GMK: green monkey kidney HAl: hemagglutination-inhibiting
82
Briefclinical and laboratory observations
The JournalofPediatrics July 1976
Table II. Serum immunoglobulin levels* and selected antibody titers'~ in a child with SHML
Antigen or immunoglobulin Poliovirus (type 1) Measles Mumps Adenovirus CytQmegalovirus Epstein-Barr virus Herpesvirus hominis IgG IgA IgM
History
Method
Booster8/25/71 Vaccine 8/24/67 Disease --/70
Neutralization HAI HAI CF CF Indirect immunofluorescence CF Radial immunodiffusion Radial. immunodiffusion Radial immunodiffusion
8/28/72 160 160 8 320 2,400 125 180
60 40 160 64 8 320 128 2,900 125 170
40 10 80
320 1,650 80 209
*Expressed as mg/dl. ~'Expressedas reciprocalsof serum dilutions. cytized hematopoietic cells. The course of the illness is protracted and benign; etiology and pathogenesis are unknown. This report describes a child with SHML who developed an exaggerated specific immune response following vaccination with attenuated rubella virus vaccine. CASE REPORT*
In December, 1970, a 6-year-old black boy was first noted to have painless cervical lymphadenopathy. In February, 1971, because of persistent lymphadenopathy, a chest radiograph and tuberculin, histoplasmin, and blastomycin skin tests were performed; all were normal In March, 1971, the child was vaccinated with HPV-77 DK/5 rubella vaccine. In April, 1971, further enlargement of the cervical lymph nodes was noted. In June, 1971, physical examination revealed massive cervical and moderate generalized lymphadenopathy. The histopathology of two cervical lymph node biopsies was diagnostic of SHML. After July, 1971, the lymph nodes gradually decreased over the fiext two years to almost normal size. Except for the lymphadenopathy, the child enjoyed good health throughout the observation period. VIROLOGIC AND SEROLOGIC
STUDIES
In June, 1971, specimens for viral studies were obtained from the nasopharynx, throat, urine, and rectum. All were cultured in African green monkey kidney, WI-38, and HEp-2 tissues cultures. Cervical lymph nodes obtained in July and October, 1971, were processed in two ways; pieces were co-cultured with HeLa, WI-38, and GMK tissue cultures and supernatant fluids of homogenates were inoculated into similar tissue cultures. All tissue cultures were observed for ~cytopathic effect through two *A more extensiveclinicalaccountof this patienthas beenreported by Lober and associatesY
blind passages. All GMK tissue cultures were tested for the presence of rubella virus by the interference technique. 3 No viruses were isolated from any of the specimens. Rubella antibody studies are presented in Table I. The highest rubella hemagglutination-inhibitingantibody titer was 1:163,840, which was noted three months after vaccination; 18 months after immunization the HAI titer was still 1:20,480. The serum specimen of October, 1971, was examined for specific IgM rubella HAI antibody by adsorption of IgG with staphylococcal protein A? Although HAI antibody was noted in the unadsorbed fraction, it accounted for only 0.02% of the total HAI antibody. On the two serums examined for both HAI and neutralizing antibodies, the HAl titers were 128- and 512fold greater than the corresponding neutralizing antibody titers. The results of other serologic tests are presented in Table II. Throughout the observation period, the child had elevated serum concentrations of IgG and IgM. With the exception of the measles HAI antibody titer which decreased from 1:160 to 1:10 in a two-month period, the titers to the other various antigens Were within expected ranges. COMMENTS The rubella HAI antibody titers noted in our patient have several possible explanations. They could be an exaggerated response to primary immunization or an unusual booster response secondary to immunization in a child with pre-existing naturally acquired antibody. Alternatively, they could be unrelated to the immunization and represent a nonspecific finding related to hypergammaglobulinemia or perhaps a specific response to an
Volume 89 Number 1
Brief clinical and laboratory observations
83
unidentified antigen that cross reacts with rubella hemagglutinin. Since antibody titers to other infectious agents (Table II) were not unusually elevated, it would seem unlikely that the rubella titers were nonspecific. A cross-reacting antigen also seems to be unlikely since this has never been described before; our patient also had high titers of rubella neutralizing antibody and possibly H A I antibody in the IgM serum component. The etiology of S H M L is unknown. Possibilities may include, however, an unknown but specific infectious process or an aberrant i m m u n e response not related to a specific infectious antigen. The response of our patient to one specific antigen would be evidence against infection as the cause of S H M L unless rubella virus was in some manner involved in the pathoge~esis. In other instances of hypertrophied lymphoid tissu'~"concomitant infections are not associated with such exaggerated antibody responses to viral antigens. ~ 7 It would seem most likely that some aberrant i m m u n e response caused a hyperreactivity or an increase in cells capable of specific antibody formation. Another possibility is that S H M L is due to an unusual response in selected individuals to rubella infection with either attenuated or wild rubella strains. Other cases
should be examined for abnormally elevated rubella titers.
Cerebrospinal fluid eosinophilia
hood multiple sclerosis, the incidence of which has been estimated to be 0.4% ~ of all cases.
A manifestation of a disorder resembling multiple sclerosis in childhood
The patient, a 10-year-old boy who was first admitted to Yale-New Haven Hospital in August of 1970, had been well until one week before admission when he developed low back pain radiating to the right lower quadrant. He developed bilateral leg weakness one day before admission. Physical examination demonstrated normal vital signs, marked nuchal rigidity, and a spastic paraparesis. There was diminished sensation to pin prick below the twelfth dermatome bilaterally. The remainder of the neurologic and general physical examinations was normal; family history and past medical history were noncontributory. Laboratory values included a normal complete blood count (with no eosinophils), skull and spine roentgenograms, and pantopaque myelography. Spinal fluid contained 82 white blood cells/ mm ~ (96% of which were lymphocytes and 4% were eosinophils), and concentrations of glucose of 54 mg/dl and protein of 56 mg/ dl. Spinal fluid protein electrophoresis revealed 47.5% gamma globulin fraction. An elect]'oencephalogram documented moderate generalized slow wave activity. Blood, cerebrospinal fluid, nasopbaryngeal, and stool cultures were all steriie for bacterial pathogens and viruses. The child received corticosteroids with
O. Carter Snead III, M.D., N e w Haven, Conn., and Steven M. Kalavsky, M.D.,* Kansas City,
Kan.
THE APPEARANCE of eosinophils in the cerebrospina! fluid is rare, particularly in the absence of peripheral eosinophilia. Also u n c o m m o n is the occurrence of childFrom the Department of Neurology and Pediatrics, Yale University and Yale-New Haven Hospital, and Department of Neurology and Pediatrics University of Kansas Medical Center. *Reprint address: Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kan. 66103.
We thank Dr. Gerrie A. Leslie for immunoglobulin determinations and Dr. Marianne Lober for patient follow-up. REFERENCES
1. Rosai J, and Dorfman RF: Sinus histiocytosis with massive lymphadenopathy: A pseudolymphomatous benign disorder, Cancer 30:1174, 1972. 2. Lober M, Rawlings W, Newell GR, and Reed RJ: Sinus histiocytosis with massive lymphadenopathy, Cancer 32:421, 1973. 3. Plotkin SA: Rubella virus, in Lennette EH, and Schmidt N J, editors: Diagnostic procedures for viral and rickettsial infections, ed 4, New York, 1969, American Public Health Association, Inc., pp 382-399. 4. Stewart GL, Parkman PD, Hopps HE, ,Dot@as RD, Hamilton JP, and Meyer HM Jr: Rubella-virus hemagglutination-inhibifion test, N Engl J Med 276:554, t967. 5. Ankerst J, Christensen P, and Kjellen L: A routine diagnostic test for IgA and IgM antibodies to rubella virus: Absorption of IgG with Staphylococcus aureus, J Infect Dis 130:268, 1974. 6. Editorial: Immnnopathology of infectious mononucleosis, Lancet 1:712, 1973. 7. Warwick WJ: The cat-scratch syndrome, many disease or one disease, Progr Med Virol 9:273, 1967.
CASE REPORT
to enteroviral infection is the case of a 3-year-old boy, from w h o m coxsackie A9 virus was recovered from swabbings of pharynx and rectum? This child showed sparing of the pupillomotor fibers, and involvement of the levator palpebrae and the four extraocular muscles innervated by the oculomotor nerve, similar to our patient. H e also recovered completely. The enteroviruses are neurotropic and may cause a variety of manifestations referable to all parts of the central and peripheral nervous systems. Coxsackie and E C H O viruses are c o m m o n causes of epidemic and sporadic lymphocytic meningitis, encephalitis associated with cranial nerve deficits including involvement of extraocular muscles2 ataxia, ~ a parkinsonian syndrome, ~ and acute ascending polyradieulomyelitis? W e would speculate that the site of viral i~(~ction in our patient was limited to the motor neurons~of the oculomotor nucleus. Acute unilateral oculomotor neuropathy with sparing of pupillomotor fibers is most likely due to a self-limited enteroviral infection. Invasive diagnostic procedures may safely be deferred if no other neurologic deficits develop.
Exaggerated antibody response following rubella vaccination in a child with sinus histiocytosis with massive lymphadenopathy Ciro V, Sumaya, M.D.,* San Antonio,
Brief clinical and laboratory observations
81
We thank Ms. Rose Rita Schlnidt, virology technician, for her assistance with the viral cultures and titer determinations. REFERENCES 1. Knox DC, Clark DB, and Schuster FF: Benign sixth nerve palsies in children, Pediatrics 40:560, 1970. 2. Saunders WH: Viral infections and cranial nerve paralysis, Arch Otolaryngol 78:101, 1963. 3. Nemet P, Ehrlich D, and Lazar M: Benign abducens palsy in varicella, Am J Ophthal 78:859, 1974. 4. Marzetti G, Midulla M, and Baldncci L: Paralisi monolaterale del III paio dei nervi craniei da virus Coxsackie A9, Minerva Pediatr 20:943, 1968. 5. Karzan DT: An epidemic of ~eptid meningitis syndrome due to ECHO virus type 6, Pediatrics 29:4i8, 1962. 6. Ravetto F, Ghidella G, and Colonna F: Acute benign ataxia referable to Coxsackie A. 5 cases observed during 1he summer of 1967, Minerva Pediatr 20:2227, 1968. 7. Waiters JH: Post-encephalitis parkmson syr~drome after meaingoencephalitis due to Coxsackie group 13, type 2, N Engl J Med 263:744, 1960. 8. Forbes SJ, Brumlik J, and Harding HB: Acute ascending polyradiculomyelitis associated with ECHO 9 virus, Dis Nerv Syst 28:537, 1970.
Table I. Serum antibody titers* to rubella virus following rubella immunization in a child with S H M L
Antibody titers Date of serum
6/71 7/71 9/71 10/71 8/72
Hemagglutinationinhibiting (HAI)~f 163,840 40,960 20,480 20,48~ 20,480
[ Neutralizing~ 80 160
*All titers are expressed as reciprocals of serum dilutions. ~Method of Stewart and associates4 with kaolin-treated serum. SPerformed by standard methods with 32 TCID~0of virus?
Texas, James D. Cherry, M.D., Los Angeles, Calif., and Robert Gohd, M.D., New Orleans, La. S I N u s I~I s T I o c,z x o s I s with massive lymphadenopathy is a recently described entity seen mainly in black chil-
From the Infectious Diseases Division, Department of Pediatrics, UCLA School of Medicine, and the Virology Laboratory, Charity Hospital at New Orleans. *Reprint address: Departmentof Pediatrics, The Universityof Texas Health Science Center at San Antonio, 7703Floyd Curl Drive, San Antonio, Texas 78284.
dren. 1 It is characterized by massive, painless, cervical lymphadenopathy, fever, hypergammaglobulinemia, and leukocytosis. The unique microscopic picture of the revolved lymph nodes features dilatation of the sinuses and numerous intrasinusal histiocytes containing phago-
Abbreviations used SHML: sinus hisliocytosis with massive iymphadenopathy GMK: green monkey kidney HAl: hemagglutination-inhibiting
82
Briefclinical and laboratory observations
The JournalofPediatrics July 1976
Table II. Serum immunoglobulin levels* and selected antibody titers'~ in a child with SHML
Antigen or immunoglobulin Poliovirus (type 1) Measles Mumps Adenovirus CytQmegalovirus Epstein-Barr virus Herpesvirus hominis IgG IgA IgM
History
Method
Booster8/25/71 Vaccine 8/24/67 Disease --/70
Neutralization HAI HAI CF CF Indirect immunofluorescence CF Radial immunodiffusion Radial. immunodiffusion Radial immunodiffusion
8/28/72 160 160 8 320 2,400 125 180
60 40 160 64 8 320 128 2,900 125 170
40 10 80
320 1,650 80 209
*Expressed as mg/dl. ~'Expressedas reciprocalsof serum dilutions. cytized hematopoietic cells. The course of the illness is protracted and benign; etiology and pathogenesis are unknown. This report describes a child with SHML who developed an exaggerated specific immune response following vaccination with attenuated rubella virus vaccine. CASE REPORT*
In December, 1970, a 6-year-old black boy was first noted to have painless cervical lymphadenopathy. In February, 1971, because of persistent lymphadenopathy, a chest radiograph and tuberculin, histoplasmin, and blastomycin skin tests were performed; all were normal In March, 1971, the child was vaccinated with HPV-77 DK/5 rubella vaccine. In April, 1971, further enlargement of the cervical lymph nodes was noted. In June, 1971, physical examination revealed massive cervical and moderate generalized lymphadenopathy. The histopathology of two cervical lymph node biopsies was diagnostic of SHML. After July, 1971, the lymph nodes gradually decreased over the fiext two years to almost normal size. Except for the lymphadenopathy, the child enjoyed good health throughout the observation period. VIROLOGIC AND SEROLOGIC
STUDIES
In June, 1971, specimens for viral studies were obtained from the nasopharynx, throat, urine, and rectum. All were cultured in African green monkey kidney, WI-38, and HEp-2 tissues cultures. Cervical lymph nodes obtained in July and October, 1971, were processed in two ways; pieces were co-cultured with HeLa, WI-38, and GMK tissue cultures and supernatant fluids of homogenates were inoculated into similar tissue cultures. All tissue cultures were observed for ~cytopathic effect through two *A more extensiveclinicalaccountof this patienthas beenreported by Lober and associatesY
blind passages. All GMK tissue cultures were tested for the presence of rubella virus by the interference technique. 3 No viruses were isolated from any of the specimens. Rubella antibody studies are presented in Table I. The highest rubella hemagglutination-inhibitingantibody titer was 1:163,840, which was noted three months after vaccination; 18 months after immunization the HAI titer was still 1:20,480. The serum specimen of October, 1971, was examined for specific IgM rubella HAI antibody by adsorption of IgG with staphylococcal protein A? Although HAI antibody was noted in the unadsorbed fraction, it accounted for only 0.02% of the total HAI antibody. On the two serums examined for both HAI and neutralizing antibodies, the HAl titers were 128- and 512fold greater than the corresponding neutralizing antibody titers. The results of other serologic tests are presented in Table II. Throughout the observation period, the child had elevated serum concentrations of IgG and IgM. With the exception of the measles HAI antibody titer which decreased from 1:160 to 1:10 in a two-month period, the titers to the other various antigens Were within expected ranges. COMMENTS The rubella HAI antibody titers noted in our patient have several possible explanations. They could be an exaggerated response to primary immunization or an unusual booster response secondary to immunization in a child with pre-existing naturally acquired antibody. Alternatively, they could be unrelated to the immunization and represent a nonspecific finding related to hypergammaglobulinemia or perhaps a specific response to an
Volume 89 Number 1
Brief clinical and laboratory observations
83
unidentified antigen that cross reacts with rubella hemagglutinin. Since antibody titers to other infectious agents (Table II) were not unusually elevated, it would seem unlikely that the rubella titers were nonspecific. A cross-reacting antigen also seems to be unlikely since this has never been described before; our patient also had high titers of rubella neutralizing antibody and possibly H A I antibody in the IgM serum component. The etiology of S H M L is unknown. Possibilities may include, however, an unknown but specific infectious process or an aberrant i m m u n e response not related to a specific infectious antigen. The response of our patient to one specific antigen would be evidence against infection as the cause of S H M L unless rubella virus was in some manner involved in the pathoge~esis. In other instances of hypertrophied lymphoid tissu'~"concomitant infections are not associated with such exaggerated antibody responses to viral antigens. ~ 7 It would seem most likely that some aberrant i m m u n e response caused a hyperreactivity or an increase in cells capable of specific antibody formation. Another possibility is that S H M L is due to an unusual response in selected individuals to rubella infection with either attenuated or wild rubella strains. Other cases
should be examined for abnormally elevated rubella titers.
Cerebrospinal fluid eosinophilia
hood multiple sclerosis, the incidence of which has been estimated to be 0.4% ~ of all cases.
A manifestation of a disorder resembling multiple sclerosis in childhood
The patient, a 10-year-old boy who was first admitted to Yale-New Haven Hospital in August of 1970, had been well until one week before admission when he developed low back pain radiating to the right lower quadrant. He developed bilateral leg weakness one day before admission. Physical examination demonstrated normal vital signs, marked nuchal rigidity, and a spastic paraparesis. There was diminished sensation to pin prick below the twelfth dermatome bilaterally. The remainder of the neurologic and general physical examinations was normal; family history and past medical history were noncontributory. Laboratory values included a normal complete blood count (with no eosinophils), skull and spine roentgenograms, and pantopaque myelography. Spinal fluid contained 82 white blood cells/ mm ~ (96% of which were lymphocytes and 4% were eosinophils), and concentrations of glucose of 54 mg/dl and protein of 56 mg/ dl. Spinal fluid protein electrophoresis revealed 47.5% gamma globulin fraction. An elect]'oencephalogram documented moderate generalized slow wave activity. Blood, cerebrospinal fluid, nasopbaryngeal, and stool cultures were all steriie for bacterial pathogens and viruses. The child received corticosteroids with
O. Carter Snead III, M.D., N e w Haven, Conn., and Steven M. Kalavsky, M.D.,* Kansas City,
Kan.
THE APPEARANCE of eosinophils in the cerebrospina! fluid is rare, particularly in the absence of peripheral eosinophilia. Also u n c o m m o n is the occurrence of childFrom the Department of Neurology and Pediatrics, Yale University and Yale-New Haven Hospital, and Department of Neurology and Pediatrics University of Kansas Medical Center. *Reprint address: Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kan. 66103.
We thank Dr. Gerrie A. Leslie for immunoglobulin determinations and Dr. Marianne Lober for patient follow-up. REFERENCES
1. Rosai J, and Dorfman RF: Sinus histiocytosis with massive lymphadenopathy: A pseudolymphomatous benign disorder, Cancer 30:1174, 1972. 2. Lober M, Rawlings W, Newell GR, and Reed RJ: Sinus histiocytosis with massive lymphadenopathy, Cancer 32:421, 1973. 3. Plotkin SA: Rubella virus, in Lennette EH, and Schmidt N J, editors: Diagnostic procedures for viral and rickettsial infections, ed 4, New York, 1969, American Public Health Association, Inc., pp 382-399. 4. Stewart GL, Parkman PD, Hopps HE, ,Dot@as RD, Hamilton JP, and Meyer HM Jr: Rubella-virus hemagglutination-inhibifion test, N Engl J Med 276:554, t967. 5. Ankerst J, Christensen P, and Kjellen L: A routine diagnostic test for IgA and IgM antibodies to rubella virus: Absorption of IgG with Staphylococcus aureus, J Infect Dis 130:268, 1974. 6. Editorial: Immnnopathology of infectious mononucleosis, Lancet 1:712, 1973. 7. Warwick WJ: The cat-scratch syndrome, many disease or one disease, Progr Med Virol 9:273, 1967.
CASE REPORT