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Human Parvovirus B19 in Children with Sickle Cell Disease; Poking the Spleen.

Parvovirus B19 (HPV B19) is a small nonenveloped single stranded DNA virus. It is highly infectious and spreads mainly through respiratory droplets. (1) Between 30-67% of patients with sickle cell disease (SCD) get infected causing transient red cell aplasia (TRCA), otherwise called aplastic crisis. (2) Moreover, HPV B19 is implicated as an etiological factor for complications escorting TRCA in patients with SCD. These complications include acute chest syndrome (ACS), hepatic sequestration, stroke, acute painful crisis, nephrotic syndrome, and acute splenic sequestration crisis (ASSC). (2) Concomitant TRCA and ASSC usually manifest in profound anemia necessitating hospital admission and blood transfusion. (3-5)

CASE REPORTS

Both patients presented to the pediatric hematology department, Sultan Qaboos University Hospital in

2014. ASSC and TRCA were diagnosed according to the Cooperative Study of Sickle Cell Disease (CSSCD) definitions:

ASSC is defined as: 1) decrease in the hemoglobin or hematocrit of [greater than or equal to] 20% from baseline; 2) evidence of increased erythropoiesis such as a markedly elevated reticulocyte count; 3) an acutely enlarging spleen ([greater than or equal to] 2 cm). (6)

TRCA is defined as: 1) decrease in hemoglobin [greater than or equal to] 20% from baseline; 2) reticulocytopenia (absolute reticulocyte count < 50 000/uL) or reticulocyte count, which is disproportionately low with respect to the hemoglobin level. (6)

Case one

A two-year-old male with homozygous sickle cell disease (Hb SS) presented with severe pallor and lethargy preceded by a one-week history of lowgrade fever, cough, and coryza. His investigations showed anemia with reticulocytopenia. He received multiple packed red blood cell (PRBC) transfusions but had a poor increment in his hemoglobin level. On day three of admission, he suddenly became pale and developed enlargement of the spleen. He was given a PRBC transfusion. His general condition gradually improved with resolution of fever.

Case two

A three-year-old male (the brother of case one) with homozygous Hb SS presented with history of fever, cough, and coryza for three days, which started one day after his younger sibling became symptomatic. On presentation, the child was pale with marked splenomegaly. His investigations revealed anemia with reticulocytopenia. He received a PRBC transfusion and was discharged.

After two days, the child became febrile with increasing pallor and severe pain in his back and limbs. Over the span of a few hours, he deteriorated with worsening of fever and pain and developed an ACS as evidenced by oxygen desaturation and new infiltrate in the chest X-ray. He was managed with PRBC transfusion. His clinical condition slowly improved over the period of two weeks.

Both patients had positive parvovirus polymerase chain reaction (PCR) with a viral load of 6.4 x 105 copies/mL and 5.9 x [10.sup.5] copies/mL for cases one and two, respectively. There was no history of ASSC, and they did not suffer another attack in a follow-up period of six months. Both children were running a mild course of the disease with infrequent admissions due to acute painful crises. Therefore, hydroxyurea treatment was not deemed indicated.

Including our two patients with SCD with concomitant TRCA and ASSC, a total of 11 patients with thoroughly described clinical parameters have been reported in the literature.

DISCUSSION

We report two cases of parvovirus infection in children with SCD presenting with concomitant TRCA and ASSC. Among the 11 cases illustrated in Table 1, two were Hb SB-thal and the rest were equally divided among Hb SS and Hb SC genotypes. Considering the overall higher incidence of Hb SS compared to Hb SC, the latter seems to be the commonest affected phenotype. (7) This finding is attributed to the relative preservation of splenic function into adulthood in patients with the Hb SC genotype and the predilection of HPV B19 infection for older children. (8,9) Such questionable hyposplenic status in patients with Hb SC genotype casts doubts regarding the need for prophylactic penicillin in early childhood. (10)

There was no age preference among the reported cases. This could be explained by the different prevalence of TRCA and ASSC during childhood. While ASSC commonly affects preschool children, TRCA is more common in older children. (11) Amongst the 11 cases reported, only one case was on hydroxyurea, which could have contributed to both their susceptibility to parvovirus infection and the ensuing reticulocytopenia. (12) It is also noteworthy that all the 11 cases had high baseline hemoglobin [greater than or equal to] 8.0 g/dL levels denoting that they had no underlying chronic hyperhemolysis.

Previous reports suggested that infection could induce ASSC. (13) The autopsy of the single mortality reported demonstrated parvovirus inclusion bodies in the spleen, which might indicate that ASSC is a direct effect of the virus on the spleen rather than an immune-mediated process. (8) Moreover, nine out of the 11 patients had no history of previous ASSC, underscoring parvovirus as a powerful stimulus for ASSC bearing in mind that a history of ASSC makes the spleen vulnerable for such a complication. (13)

In our two cases, the chronology of events described suggests that TRCA might have ensued before the ASSC. Additionally, one of these two cases developed ACS. Such a case when summed with three other reported cases in the literature, two with multiorgan dysfunction syndrome and one death, demonstrate the possible gravity of prognosis of such a combined pathology. (4,5)

A large epidemiological study was carried out between November 1996 and December 2001, which screened 633 SCD patients for HPV B19 infection. Among the 68 patients who developed TRCA episodes during the study period, 13 had evidence of concomitant TRCA and ASSC. Of these, four had the Hb SS genotype, seven were Hb SC, and two were Hb SB-thal. The study showed that children acutely infected with HPV B19 were more likely to develop fever, painful crises, and ASSC than uninfected children. (2) Consistent with other reports, the study also revealed that patients with SCD SC had more ASSC events compared with the SCD SS group. (3-5) Unfortunately, clinical and laboratory data specific to the group of concurrent ASSC and TRCA were not segregated from the rest of the study group. The clinical parameters of the remaining nine patients along with our two reported cases are given in Table 1.

How parvovirus causes TRCA in children with SCD has been the subject of intensive studies. The virus targets erythroid progenitor cells with the blood group P antigen serving as the receptor for the virus. Poor P antigen expression by megakaryocytes and white blood cells explains the rare incidence of thrombocytopenia or leucopenia in HPV B19 infection. (14) The infected erythroid precursors suffer arrest of maturation beyond the normoblast stage leading to the formation of giant pronormoblasts in the bone marrow and peripheral reticulocytopenia. (15,16) Such reticulocytopenia tend to be transient and clinically silent in healthy persons. (17) On the other hand, this transient reticulocytopenia augments the existing anemia in patients with a shortened erythrocyte life span, such as SCD, resulting in a further drop in hemoglobin and symptomatic anemia. (18) The concurrence of ASSC further complicates the picture. While hemoglobin in patients affected solely by TRCA is dependent upon surviving mature red blood cells, these get pooled inside the spleen and escalate the ongoing hemoglobin drop in patients with combined pathologies. The development of ASSC turns the clinical picture into an emergency situation. In contrast to TRCA, where anemia develops over days, the drop of hemoglobin in ASSC happens in a matter of hours. (19) The coexistent peripheral destruction along with central aplasia of the erythroid cell line might result in serious anemia. It is readily conceivable that ASSC and TRCA can form a deadly combination bearing in mind that ASSC alone can induce circulatory collapse. (20) The exact pathophysiology of ASSC is unknown. Fever or infection may trigger or augment red cell trapping in the splenic red pulp. (21) None of the previous reports of concomitant ASSC and TRCA have postulated a clear mechanism.

CONCLUSION

Parvovirus infection presenting with concomitant TRCA and ASSC is an uncommon but potentially serious complication in children with SCD. Therefore, we strongly recommend that patients who present with TRCA to be closely observed for evolving ASSC. Any child with SCD who presents with a sudden drop in hemoglobin, reticulocytopenia, and an acute enlargement of spleen should be managed as a potentially life-threatening emergency.

Disclosure

The authors declared no conflicts of interest.

REFERENCES

(1.) Young NS, Brown KE; Parvovirus B19. Parvovirus B19. N Engl J Med 2004 Feb; 350(6):586-597.

(2.) Smith-Whitley K, Zhao H, Hodinka RL, Kwiatkowski J, Cecil R, Cecil T, et al. Epidemiology of human parvovirus B19 in children with sickle cell disease. Blood 2004 Jan; 103(2):422-427.

(3.) Mallouh AA, Qudah A. Acute splenic sequestration together with aplastic crisis caused by human parvovirus B19 in patients with sickle cell disease. J Pediatr 1993 Apr; 122(4):593-595.

(4.) Wethers DL, Grover R, Oyeku S. Aplastic crisis and acute splenic sequestration crisis. J Pediatr Hematol Oncol 2000 Mar-Apr; 22(2):187-188.

(5.) Yates AM, Hankins JS, Mortier NA, Aygun B, Ware RE. Simultaneous acute splenic sequestration and transient aplastic crisis in children with sickle cell disease. Pediatr Blood Cancer 2009 Sep; 53(3):479-481.

(6.) Ballas SK, Lieff S, Benjamin LJ, Dampier CD, Heeney MM, Hoppe C, et al; Investigators, Comprehensive Sickle Cell Centers. Definitions of the phenotypic manifestations of sickle cell disease. Am J Hematol 2010 Jan; 85(1):6-13.

(7.) Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood 2010 Jun; 115(22):4331-4336.

(8.) Hannemann A, Weiss E, Rees DC, Dalibalta S, Ellory JC, Gibson JS. The Properties of Red Blood Cells from Patients Heterozygous for HbS and HbC (Hb SC Genotype). Anemia. 2011; 2011:248527.

(9.) Ware R. Human parvovirus infection. J Pediatr 1989 Mar; 114(3):343-348.

(10.) Lane PA, O'Connell JL, Lear JL, Rogers ZR, Woods GM, Hassell KL, et al. Functional asplenia in hemoglobin SC disease. Blood 1995 Apr; 85(8):2238-2244.

(11.) Kinney TR, Ware RE, Schultz WH, Filston HC. Long-term management of splenic sequestration in children with sickle cell disease. J Pediatr 1990 Aug; 117(2 Pt 1):194-199.

(12.) Princeton NJ. Hydroxyurea, Bristol Myers Squibb Company Package insert, 2011.

(13.) Brousse V, Elie C, Benkerrou M, Odievre MH, Lesprit E, Bernaudin F, et al. Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. Br J Haematol 2012 Mar; 156(5):643-648.

(14.) Brown KE, Anderson SM, Young NS. Erythrocyte P antigen: cellular receptor for B19 parvovirus. Science 1993 Oct; 262(5130):114-117.

(15.) Owren PA. Congenital hemolytic jaundice; the pathogenesis of the hemolytic crisis. Blood 1948 Mar; 3(3):231-248.

(16.) Singer K, Motulsky AG, Wile SA. Aplastic crisis in sickle cell anemia; a study of its mechanism and its relationship to other types of hemolytic crises. J Lab Clin Med 1950 May; 35(5):721-736.

(17.) Anderson MJ, Higgins PG, Davis LR, Willman JS, Jones SE, Kidd IM, et al. Experimental parvoviral infection in humans. J Infect Dis 1985 Aug; 152(2):257-265.

(18.) Saarinen UM, Chorba TL, Tattersall P, Young NS, Anderson LJ, Palmer E, et al. Human parvovirus B19-induced epidemic acute red cell aplasia in patients with hereditary hemolytic anemia. Blood 1986 May; 67(5):1411-1417.

(19.) Okpala IE. Sickle cell crisis. In: Okpala IE, editor. Practical management of haemoglobinopathies. 1st ed. Blackwell Publishing; 2004. p. 63-71.

(20.) Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug P, Rida W; Cooperative Study of Sickle Cell Disease. Mortality in children and adolescents with sickle cell disease. Pediatrics 1989 Sep; 84(3):500-508.

(21.) Brousse V, Buffet P, Rees D. The spleen and sickle cell disease: the sick(led) spleen. Br J Haematol 2014 Jul; 166(2):165-176.

Ashraf Abdellah Saad [1], Ismail Beshlawi [1,2] *, Abdul Hakim Al-Rawas [1], Mathew Zachariah [1], Hanan Fawzy Nazir [1] and Yasser Wali [1]

[1] Child Health Department, Sultan Qaboos University Hospital, Muscat, Oman

[2] Nottingham Children's Hospital, Nottingham University Hospital Trust, Nottingham, UK

Online:

DOI10.5001/omj.2017.79

ARTICLE INFO Article history:

Received: 31 January 2016 Accepted: 2 May 2016
Table 1: Clinical parameters of11 patients with SCD with concomitant
ASSC and TRCA.

Clincal                                 Case no.
parameters
                       1       2       3       4       5        6

Genotype             Hb SS   Hb SS   Hb SS   Hb SS   Hb SS    Hb SC
Age                   22m     8y      10y     4m      3y       8y
Gender                 M       F       F       M       F        F
On prsentation
  Spleen size, cm#     5      10       7       7       6        4
  Hb, g/dL            1.6     2.0     4.5     1.1     3.7      4.3
  Reticulocytes       0.1     0.6     0.3     NA      0.1      0.2
  Platelets, x        72      97      125     72      48       108
    [10.sup.9]/L
Baseline
  Spleen size, cm      1       2       3       2      NA       NA
  Hb, g/dL           10.0    10.7    10.0     NA      9.2      NA
  Parvovirus IgM      +ve     +ve     +ve    -ve*     +ve      +ve
  Complications      Coma,   None     --     Coma,   None    Painful
                     shock                   shock           crisis
                                             death
References             3      --      --       4       5       --

Clincal                             Case no.
parameters
                       7       8       9       10       11

Genotype             Hb SC   Hb SC   Hb SC   Hb SS    Hb SS
Age                   15y     11y     6y      22m       3y
Gender                 F       M       M       M        M
On prsentation
  Spleen size, cm#     7      10      10       6        11
  Hb, g/dL            3.9     3.9     4.2     2.7      7.1
  Reticulocytes       0.1     0.4     0.4     0.8      0.2
  Platelets, x        40      85      100     104       64
    [10.sup.9]/L
Baseline
  Spleen size, cm     NA      NA      NA       2        4
  Hb, g/dL           11.4    10.3    10.4     8.0      10.0
  Parvovirus IgM      +ve     +ve     +ve     +ve      +ve
  Complications      MODS     --     None     None     None

References            --      --      --     Case 1   Case 2

SCD: sickle cell disease; ASSC: acute splenic sequestration crisis;
TRCA: transient red cell aplasia; M: male; F:female; NA: not
available; Hb: hemoglobin; IgM: immunoglobulin M; MODS: multiple
organ dysfunction syndrome. *Evidence of infection was demonstrated
by parvovirus B19 inclusion bodiesfound in the spleen at autopsy.
#Clinicalpalpable spleen below the left costal margin along the
midclavicular line.
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Title Annotation:CASE REPORT
Author:Saad, Ashraf Abdellah; Beshlawi, Ismail; Rawas, Abdul Hakim Al-; Zachariah, Mathew; Nazir, Hanan Faw
Publication:Oman Medical Journal
Article Type:Report
Date:Sep 1, 2017
Words:2334
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