Occult And Human J Am Board Fam Pract: first published as 10.3122/jabfm.4.6.461 on 1 November 1991. Downloaded from Parvovirus Infection

Anne Cather Cutlip, M.D., KarenM. Gross, M.D., andMichaelj. Lewis, M.D., Ph.D.

The human parvovirus (HPV) is believed to be sient mild jaundice, and splenomegaly (usually the causative agent of infectiosum, or associated with viral syndromes); (2) aplastic crisis, fifth disease. 1 Transient aplastic crisis linked to with nausea, vomiting, abdominal pain, and head­ HPV infection has been described in several types ache (also associated with viral syndromes), typi­ of hemolytic anemias, congenital or acquired, cally lasting 10 to 14 days, with the hemoglobin such as , thalassemia, auto­ falling to approximately one-half of the usual immune hemolytic anemias, and hereditary valuell; or (3) megakJblastic crisis secondary to in­ spherocytosis.2-8 In some instances, the underly­ sufficient dietary intake of folic acid for increased ing was not recognized until needs (such as seen during ).u the patient developed transient aplastic crisis sec­ We report a patient with previously undiag­ ondary to HPV infection. The B19 HPV has a nosed hereditary spherocytosis who presented propensity for the erythrocyte progenitor cells, to with an aplastic crisis resulting from an HPV which it is cytotoxic.7 It is generally believed that infection. Considerations for diagnosing this in­ a decrease in erythroblasts occurs in all patients fection and treating patients with unexpected on first contact with HPV B19, but a crisis reveals aplastic crisis are discussed. itself only in patients whose erythrocytes have an inherent shortened life span (as in some hemo­ Case Report lytic anemias). A 23-year-old white woman who had been in

Hereditary spherocytosis is the most common good health had a 3-day history of aching low­ copyright. hemolytic anemia in persons of Northern Euro­ back pain, arthralgias, fever, nausea, vomiting, pean extraction, occurring in 1 person in 5000.9 and diffuse abdominal pain. She was seen 1 day Although classically believed to be autosomal before admission to the hospital and was thought dominant in inheritance, 20 to 25 percent of pa­ to have gastroenteritis. On the following day she tients with hereditary spherocytosis have normal complained of the same symptoms, as well as parents, raising the question of mutation, incom­ some dyspnea on exertion. Her temperature was

plete penetrance, or recessive forms of the dis­ 37°C (98.6°F), pulse rate 96 beats per minute, and http://www.jabfm.org/ ease.9 The red cells of patients with hereditary pressure 120/80 mmHg. Head, neck, chest, spherocytosis have a membrane defect causing skin, and neurological examinations were normal. decreased cell surface area, leading to a spheroidal Her heart rate and rhythm were regular, and she shape and osmotically fragile cells. Selectively had a grade IIIVI systolic ejection murmur with­ trapped by the spleen, these cells have a shortened out radiation. Her abdomen was soft with active life span. The most common complication is gall­ bowel sounds and mild tenderness in both the bladder disease, with 55 to 85 percent of un­ right upper and right lower quadrants, without on 25 September 2021 by guest. Protected treated patients eventually developing pigment rebound. A spleen tip was palpable. Pelvic exami­ gallstones. 10 nation showed cervical motion tenderness, bilat­ Patients with hereditary spherocytosis may eral adnexal tenderness, and a yellowish vaginal develop one of three types of crises, including discharge. Laboratory studies showed her to (1) mild hemolytic crisis, with mild anemia, tran- be leukopenic (white cell count, 4.2 X 1091L [42oo/mm 3]) and anemic (hemoglobin, 81 gIL [8.1 g/dL]), with a white cell differential of 0.02 Submitted, revised, 28 June 1991. band cells, 0.79 neutrophils, 0.01 eosinophils, From the Department of Family Medicine, West Virginia 0.16 lymphocytes, and 0.02 monocytes. No com­ University, Morgantown. Address reprint requests to Anne C. Cutlip, M.D., Department of Family Medicine, WVU-Health ment was made on red cell morphology on the Sciences Center, Morgantown, WV 26506. initial peripheral smear. Electrolytes were nor-

Occult Hereditary Spherocytosis 461 mal, and blood urea nitrogen was 10 mmollL (27 parvovirus B 19 by enzyme-linked immunoassay J Am Board Fam Pract: first published as 10.3122/jabfm.4.6.461 on 1 November 1991. Downloaded from mg/dL; nonnal 10 to 20 mg/dL). Total bilirubin technique "consistent with recent infection." She was 52 jJJIlollL (3.0 mg/dL) , and conjugated continued to do well and 3 months after discharge bilirubin was 20 J.LmollL (1.2 mg/dL). Serum underwent cholecystectomy and splenectomy amylase was nonnal, and erythrocyte sedimenta­ after receiving pneumococcal vaccine. Subse­ tion rate was elevated to 41 mmIh. Urinalysis quent studies of her family showed hereditary showed trace amounts of protein and ketones and spherocytosis in her father, sister, niece, and bilirubinemia (1 +). nephew. She was admitted to the hospital with a diagno­ sis of anemia, probably secondary to hemolysis, Discussion and acute pelvic inflammatory disease. Results of The human parvovirus, the smallest DNA­ repeat laboratory studies after admission were he­ containing animal , is a single-stranded moglobin 61 gIL, platelet count 127 X 1091L DNA, nonenveloped virus. It requires actively (127 X 103/mm3), and a corrected reticulocyte dividing cells for autonomic replication; there­ count 0.001 (0.1 percent). Serum haptoglobin fore, the bone marrow is a "favorable milieu." was less than 0.05 gIL (5 mg/dL; nonnal 27- HPV was originally discovered in the blood of 9 139 mg/dL), and Coombs tests (direct and indi­ healthy donors during evaluation of second-gen­ rect) were negative. Liver enzymes were nonnal eration tests for surface antigen. 13 A with the exception of an elevated lactate dehydro­ viruslike particle 23 nm in diameter was revealed genase (5.46 J.LKatIL [328 UIL]). Initially, by electron microscopy and was originally labeled intravenous doxycycline therapy was started; B 19 or parvoviruslike agent or serum parvovirus­ however, because a persistent fever and a decreas­ like virus. 14 ing white cell count (2.5 X 1091L) raised a ques­ HPV infection is common worldwide, and it tion of sepsis, ampicillin and gentamicin were usually occurs in children of primary school age. IS added. She developed a generalized, non­ The antibody is detectable most often in children pruritic macular after the first dose of ampi­ between the ages of 4 and 10 years, and studies copyright. cillin, and her antibiotic was then changed to report a seroprevalence from 2 to 15 percent in cefoxitin. children aged 1 to 5 years and from 30 to 60 Bilateral iliac bone marrow aspirates and biop­ percent in adults.16 The respiratory tract is sies showed with nonnal the most likely portal of entry, although blood megakaryocyte and myeloid cells, consistent with products can also transmit the virus. HPV spreads an infectious process. The Ham test was negative, easily among children within families, with an

as were tests for disseminated intravascular estimated 50 percent attack rate in susceptible http://www.jabfm.org/ coagulopathy. The peripheral smear contained household contacts. IS Annual and seasonal (win­ spherocytes, and osmotic fragility testing was in­ ter, spring) variations are noted. creased, diagnostic of hereditary spherocytosis. HPV is believed to be the causal agent of the While hospitalized, the patient required transfu­ erythema infectiosum (fifth disease), a sion of five units of packed red cells. Ultra­ febrile illness with mild flulike symptoms, a typi­ sonography of her right upper quadrant revealed cal rash on the face (described as "slapped-cheek" on 25 September 2021 by guest. Protected numerous gall stones and "sludge." Findings on in appearance), and a lacey, reticulated rash on the her pelvic examination returned to nonnal. Blood trunk and extremities. Up to 20 percent of infec­ cultures were negative, as were cervical cultures tions are asymptomatic. The of for Neisseria g01lO1Thoeae and Chlamydia. Her erythema infectiosum is 4 to 14 days based upon blood count improved; at time of discharge, studies of secondary household infections. Studies her hemoglobin was 123 gIL; white cell count was in volunteers have reported onset of the rash 17 8.6 X 1091L, reticulocyte count was 0.014; and to 18 days after inoculation. 16 she was afebrile and feeling well. Although benign infection with HPV is the Serum samples obtained from the patient usual case, adults can occasionally develop a self­ 6 weeks after onset of illness were sent to the limited, moderately severe symmetrical periph­ Centers for Disease Control (CDC). They eral polyarthropathy, primarily involving the showed both IgG and IgM antibodies to human hands, wrists, and kneesP No recent literature

462 ]ABFP Nov.-Dec. 1991 Vol. 4 No.6 supports an association between pelvic inflamma­ hereditary spherocytosis. Lefrere and colleagues8 J Am Board Fam Pract: first published as 10.3122/jabfm.4.6.461 on 1 November 1991. Downloaded from tory disease symptoms and HPV infection. Severe have concluded that in a previously healthy pa­ complications of the infection are also known. tient who experiences an aplastic crisis that is due The virus appears to have the potential to be to HPv, the diagnosis of hereditary spherocytosis embryocidal, although not teratogenic. 18.19 Fetal should be investigated. infection can cause severe anemia, congestive The diagnosis of HPV infection is made by heart failure, fetal hydrops, and death,15.19-21 demonstrating the virus by electron microscopy A study from the United Kingdom found the risk or by demonstrating seroconversion ofIgM class­ of fetal death to be up to 10 percent during the specific antibodies to HPV in a recovering patient 10th to 20th weeks of pregnancy.22 Congenital by enzyme-linked immunoassay or radioimmu­ anomalies after B 19 infection in the mother do noassay techniques. IgM antibodies are present in not seem to occur.23.24 approximately 90 percent of cases by the 3rd day HPV is cytotoxic to erythrocyte progenitors, after onset of symptoms of erythema infectiosum and although this cell line is the main target, other or transient aplastic crisis and decline 30 to 60 cell lineages also can be involved, causing days after onset. IgG antibodies appear by the 7th thrombocytopenia and, less often, leukopenia. In day of illness and persist for years. Transmission immunocompromised patients, chronic infection electron microscopy can demonstrate inclusions with HPV can cause a persistent and severe containing parvoviruslike particles, where light anemia.25 microscopy of the erythroid precursor cells shows It is well known that patients with chronic eosinophilic nuclear inclusions and chromatin hemolytic anemia can develop episodes of peripherally. medullary aplasia of brief duration and spon­ The CDC has submitted guidelines in Morbid­ taneous resolution (transient aplastic crises) in ity and Mortality weekly Report for preventing association with infections, particularly of vi­ HPV infection and caring for persons exposed to

ral origin. Several studies have reported this or infected with the virus. It was believed that copyright. occurrence in patients with known occult dis­ those patients with clinical erythema infectiosum eases, such as sickle cell disease, hereditary are no longer infectious, and isolation procedures spherocytosis, various thalassemias, and pyruvate are not needed for them. Patients with transient kinase deficiency. Aplastic crises associated aplastic crisis or immunodeficient patients with with HPV infection are commonly accompa­ chronic anemia should be considered to be in­ nied by fever, headache, abdominal pain, general­ fectious. Masks are suggested, as well as gloves ized fatigue and weakness, nausea, vomiting, and gowns, if a caretaker is likely to have con­ and rigors. tact with respiratory tract secretions. 15 A study of http://www.jabfm.org/ It has been postulated that aplasia can occur in two separate outbreaks of illness resembling normal persons, but because of normal red cell erythema infectiosum occurred recently in a survival and short duration of the illness, such hospital setting. Two immunocompromised episodes go unnoticed. The crisis is more readily patients, both with sickle cell disease and tran­ detected in the immunocompromised person.7 sient aplastic crisis, had suspected and later

Mortimer26 conducted a.retrospective study of 16 proved HPV infection. Attack rates of susceptible on 25 September 2021 by guest. Protected reports published between 1935 and 1984 and contacts were 36 to 38 percent, with development concluded that HPV was the primary cause of of clinical symptoms in an average of 12.6 days,27 aplastic crises occurring in patients with heredi­ The authors' recommendation was that all tary spherocytosis. To support his hypothesis, he patients with hereditary hemolytic anemias who pointed out that these patients had no history of are admitted for febrile illness be evaluated aplastic crisis attacks, and the interval between for aplasia and promptly placed in respiratory index and other cases was relatively constant at and contact isolation if an aplastic crisis is sus­ approximately 9 days. Also, the duration of the pected. In the nonhospital environment, there are aplastic crisis was regular and invariable at 10 to fewer options for decreasing transmission of 12 days after onset. Kelleher, et al.3 also have the virus. The efficacy of hand washing and shown that HPV is serologically linked to aplastic decontamination of toys and environmental crisis in a population of pediatric patients with surfaces has not been studied.

Occult Hereditary Spherocytosis 463 Conclusion 12. Kohler HG, Meynell MI, Cooke wr. Spherocytic J Am Board Fam Pract: first published as 10.3122/jabfm.4.6.461 on 1 November 1991. Downloaded from This report presents a case of occult hereditary anemia, complicated by megaloblastic anemia of 1 spherocytosis diagnosed after the patient de­ pregnancy. Br MedJ 1960; 1:779-81. 13. Cossart YE, Field AM, Cant B, Widdows D. veloped an aplastic crisis resulting from an acute Parvovirus-like particles in human sera. Lancet I human parvovirus infection. We believe that it is I 1975; 1:72-3. i 1 important for physicians to be aware of the rela­ 14. Anderson MI, Pattison JR. The human parvovirus. i tion between HPV infection and aplastic crises in Briefreview. Arch Vrro11984; 82:137-48. patients with various chronic hemolytic anemias. 15. Anderson MJ, Higgins PG, Davis LR, WIllman JS, Jones SE, Kidd 1M, et al. Experimental parvovirus infection in humans. J Infect Dis 1985; References 152:257-65. 1. Anderson MJ, Lewis E, Kidd 1M, Hall SM, Cohen 16. Leads from the MMWR. Risks associated with BJ. An outbreak of erythema infectiosum associated human infection. JAMA 1989; 261: with human parvovirus infection. J Hyg 1984; 93: 1406-8, 1555, 1560, 1563. 85-93. 17. White DG, Woolf AD, Mortimer pp, Cohen BJ, 2. Rao KR, Patel AR, Anderson MI, HodgsonJ, Jones Blake DR, Bacon PA Human parvovirus arthropa­ SE, PattisonJR. Infection with parvovirus-like virus thy. Lancet 1985; 1:419-21. and aplastic crisis in chronic hemolytic anemia. Ann 18. Rodis JF, Hovick 1] Jr, Quinn DL, Rosengren SS, Intern Med 1983; 98:930-2. Tattersall P. Human parvovirus infection in preg­ 3. Kelleher JF, Luban NL, Mortimer pp, Kamimura T. nancy. Obstet Gyneco11988; 72:733-8. Human serum "parvovirus": a specific cause of aplas­ 19. Mead PB. Parvovirus B19 infection and pregnancy. tic crisis in children with hereditary spherocytosis. J Contemp OB/GYN 1989; 34:56-70. Pediatr 1983; 102:720-2. 20. Brown T, Anand A, Ritchie LD, Clewley JP, Reid 4. Lefrere J], Courouce AM, Girot R, Bertrand Y, TM. Intrauterine parvovirus infection associated Soulier JP. Six cases of hereditary spherocytosis re­ with . Lancet 1984; 2:1033-4. vealed by human parvovirus infection. Br J 21. Anand A, Gray ES, Brown T, Clewley JP, Cohen BJ. Haematol1986; 62:653-8. Human parvovirus infection in pregnancy and 5. Lefrere J], Courouce AM, Girot R, Cornu P. Human hydrops fetalis. N EnglJ Med 1987; 316:183-6.

parvovirus and thalessaemia.J Infect 1986; 13:45-9. 22. Public health laboratory service working party on copyright. 6. Gowda N, Rao Sp, Cohen B, Miller ST, Clewley JP, fifth disease. Study of human parvovirus (B19). Brown A. Human parvovirus infection in patients Infection in pregnancy. Comm Dis Rep 1987; with siclde cell disease with and without hypoplastic 87: 20-3. crisis.J Pediatr 1987; 110:81-4. 23. KinneyJS, Anderson LJ, FarrarJ, Strikas RA, Kumar 7. Young NS, Mortimer pp, Moore JF, Humphries RK. ML, Kliegman RM, et al. Risk of adverse outcomes Characterization of a virus that causes transient of pregnancy after human parvovirus B19 infection. aplastic crisis. J Clin Invest 1984; 73:224-30. J Infect Dis 1988; 157:663-7. 8. Lefrere JJ, Courouce AM, Bertand Y, Girot R, 24. Mortimer pp, Cohen BJ, Buckley MM, Craddock­ Soulier JP. Human parvovirus and aplastic crisis in Watson JE, Ridehalgh MK, Burkhardt F, et al. http://www.jabfm.org/ chronic hemolytic anemias: a study of 24 observa­ Human parvovirus and the fetus. Lancet 1985; tions. AmJ Hemato11986; 23:271-5. 2:1012. 9. Morton NE, Mackinney AA, Kosower N, Schilling 25. Kurtzman G, Frickhofen N, KimballJ, Jenkins DW, RF, Gray MP. Genetics of spherocytosis. Am J Hum Neinhuis AW, Young NS. Pure red-cell aplasia of 10 Genet 1962; 14:170. years' duration due to persistent parvovirus B19 in­ 10. Lux SE, Becker PS. Disorders of the red cell mem­ fection and its cure with immunoglobulin therapy. N

brane skeleton: hereditary spherocytosis and heredi­ EnglJ Med 1989; 321:519-23. on 25 September 2021 by guest. Protected tary elliptocytosis. In: Scriver CR, Beaudet AL, 26. Mortimer PP. Hypothesis: the aplastic crisis of he­ Sly WS, Valle D, editors. The metabolic basis of in­ reditary spherocytosis is due to a single transmissible herited disease. New York: McGraw-Hill, 1989: agent. J Clin Patho11983; 36:445-8. 2367-408. 27. Bell LM, Naides SJ, Stoffman P, Hodinka RL, Plot­ 11. Owren PA Congenital hemolytic jaundice. The kin SA Human parvovirus B19 infection among pathogenesis of the "hemolytic crisis." Blood 1948; hospital staff members after contact with infected 3:231-48. patients. N EnglJ Med 1989; 321 :485 -91.

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