تشخیص

Hyper IGM
Pneumo Cystis Carinii Pneumonia P.C.P

Arthritis as an uncommon manifestation of Hyper Ig M syndrome

A 9-month old male infant presented to the emergency department with a 20-days history of cough, sneeze, couriza and fever. He presented swelling of left knee with normal range of motion since 15 days ago. His fever increased and he admitted at other hospital before admission at our hospital and treated as septic arthritis there.

He suddenly presented respiratory failure after dranage of his knee and referred to our hospital and admitted in ICU.

He presented cough and respiratory distress at 2 month-old but responded to usual treatment. After that he had frequently common cold manifestation that responded to usual treatments.

He was born at 38 weeks gestation with a birth weight of 3200 gr after uncomplicated pregnancy, delivery and nursery course. He resided with his mother, father, 2 siblings: His healthy sister and his 10-year-old brother who presented arthritis at 3 years of his life. He presented hematuria , proteinuria , priorbital edema  and renal failure and admitted in ICU since 3 month ago.

On examination, the infant had a temperature of 38.5 'c, a pulse of 96 beats/min, a respiratory rate of 54/min and a weight of 8.5 kg, with an oxygen saturation of 80.5% in room air. He was lethargic and had subcostal and intercostals retraction in chest examination, fine crackle in the base of both lungs. 

    A chest radiograph showed diffused alveolar consolidation with airbronchogram. Hematologic studies revealed a white cell count of 25,800/mm3 with a differential count of 57% neutrophils, 43%  lymphocyte ; hemoglobin 14.4 g/dl; and platelet count 699,000/mm3.

Blood and urine cultures were obtained, synovial fluid contained many white cell count with no bacteria. Synovial fluid culture was negative.

  The electrolytes, urine analysis were all normal. Only LDH level showed rising to 1287     .

The patient was hospitalized and empirically treated with

Co-trimoxazole, ceftriaxone,  cloxacillin.

 Bronchial alveolar lavage showed Ecoli. An open lung biopsy was performed which revealed the etiology of this infant's illness.

Denouement

Key Words: arthritis, hyper IgM syndrome, pneumocystis carinii

Prompted by the unusual radiographic findings, an immunology evaluation was performed. Quantitative immunoglobulins were including IgG, IgA,IgM,IgE and complements (C3, C4). C3 and C4 were normal.

Flowcytometry  Immunophentyping Analysis: CD3,CD4,CD8 ,CD1(1b),CD1(1c),CD16,CD56,CD11c were decreased. CD1 (1a), CD19 were increased. CD18, CD11a, CD11b were normal. NBT test was normal. HIV Ab/Ag was non reactive.

Ig M was increased, Ig G, Ig A were decreased. IgE was normal.

His brother immunoglobulin test shows high IgM level.

The open lung biopsy revealed healing ARDS with pneumocystis carinii cysts.

A diagnosis of Hyper IgM syndrome with pneumocytis carinii  pneumonia was made. Therapy with ceftriaxone was initiated. The patient was also given trimethoprim-sulfamethoxazole and IVIG.  Repeating chest radiography showed improvement after 17 days. He currently receives monthly IVIG and prophylactic trimethoprim-sulfamethoxazole and he is currently free of infection.   First described by Rosen et al in 1961, XHIGM is an inherited immunodeficiency resulting in a defect in immunoglobulins function. Immunodeficiency with hyper-IgM was described by Israel-Asselain et al. in 1960  and Rosen et al. in 1962.In 1974, a World Health Organization (WHO) working party named the syndrome immunoglobulin deficiency with increased IgM (hyper-IgM syndrome [HIGM])[3].

 It is characterized by recurrent infections, very low or undetectable levels of IgG and IgA, normal to increased serum IgM[4].

   Approach to Diagnosis[5]

The primary immunodeficiencies characteristically present in childhood with infections that persist for long duration with multiple recurrences that are resistant to antibiotics. Failure to thrive and developmental delay are significant clues to the seriousness of their infections. Many immunodeficient children develop other symptoms such as skin rashes, and many have associated developmental anomalies of the face, skeletal system, heart, and pigmentation[5].

The nature of the pathogens and sites of infections can provide insight as to the underlying immunodeficiency. Defects involving B cell function result in recurrent sinopulmonary infections, often with bacterial septicemia. The lack of antibody production may also increase susceptibility to invasive disease with enteroviruses, resulting in chronic viral meningitis, and giardiasis. T cells are essential for the control of viral and fungal disease, however they also provide helper function to B cells for effective antibody responses. Thus, T cell disorders present as combined T and B cell immunodeficiency with susceptibility to both bacterial and chronic, invasive viral, and fungal pathogens. Patients with disorders of granulocytes are susceptible to staphylococcal diseases and gram-negative infections[5].

The primary immunodeficiencies are commonly inherited disorders, thus a family history is one of the best diagnostic clues. Unfortunately, because these diseases are rare with low carrier frequencies, a negative family history does not rule out a primary immunodeficiency. Furthermore, occurrence of new mutations, especially for X-linked disorders, is so high that the majority of patients with proven X-linked immunodeficiency mutations have no history of affected male relatives[5].

 
Initial laboratory evaluation for immunodeficiency should include a minimum of tests that can be performed reliably by any laboratory[6]. The initial screening should include a complete blood count and quantitation of serum IgG, IgM, and IgA levels. Laboratories should provide age-matched normal values for cell counts, immunoglobulin measurements and proper controls for functional studies. Other readily available tests are: 1) Quantification of blood mononuclear cell populations: T cells (CD3, CD4, CD8, TCR ß, TCR ); B cells (CD19, CD20, CD21, Ig); NK cells (CD16/CD56); monocytes (CD15); activation markers (HLA-DR, CD25, CD80 for B cells), CD154 for T cells. 2) T cell functional evaluation: delayed hypersensitivity skin tests (PPD, Candida, histoplasmin, and tetanus toxoid); proliferative response to mitogens (anti-CD3 antibody, phytohemagglutinin, concanavalin A) and allogeneic cells (mixed lymphocyte response); cytokine production. 3) B cell functional evaluation: natural or commonly acquired antibodies; response to immunization proteins and carbohydrate antigens; and quantitative IgG subclass determination. 4). Phagocyte function: reduction of nitroblue tetrazolium; chemotaxis assays, and bactericidal activity[5].

 The benefit of immunoglobulin (IG) replacement in primary antibody deficiencies is unquestionable[7].

Treatment of XHIM is based on regular administration of i.v. immunoglobulins and use of cotrimoxazole to prevent PCP [8]. Severe neutropenia responds to administration of recombinant granulocyte colony-stimulating factor (G-CSF) [9]. Prevention of liver disease is based on careful monitoring of liver function, and on hygienic measures to avoid Cryptosporidium infection (i.e. use of boiled or bottled water).

Despite all these measures, the mortality rate remains very high in XHIM, and more aggressive forms of treatment have been proposed. Liver transplantation has been attempted in a few cases with sclerosing cholangitis, but relapse is common [8]. In contrast, bone marrow transplantation (particularly if performed early in life) from HLA-identical family (and possibly also from matched unrelated) donors may cure the disease [8,10].

REFERENCES

1.Israel-Asselain, R; Burtin, P; Chebat, J. Un trouble biologique nouveau: 1.L'agammaglobulinémie avec beta2-macroglobulinémia (un cas). Bull Soc Med Hop Paris. 1960;76:519–23.

2.Rosen, FS; Kevy, SV; Merler, E; Janeway, CA; Gitlin, D. Recurrent bacterial infections and dysgammaglobulinemia. Deficiency of 7S gammaglobulins in the presence of elevated 19S gammaglobulins. J Pediatr. 1961;28:182–95.

3.Cooper MD, Faulk WP, Fudenberg HH, et al. Meeting report of the Second International Workshop on Primary Immunodeficiency Disease in Man held in St. Petersburg, Florida, February, 1973. Clin Immunol Immunopathol. Apr 1974;2(3):416-45.

4.Notarangelo, LD; Duse, M; Ugazio, AG. Immunodeficiency with hyper-IgM (HIM). Immunol Rev. 1992;3:101–21.

 5.Lim MS, Elenitoba-Johnson KSJ: The molecular pathology of primary immunodeficiencies. Mol Diagn J 2004, 6:59-83.

 6. Tangsinmankong N, Bahna SL, Good RA: The immunologic workup of the child suspected of immunodeficiency. Ann Allergy Asthma Immunol 2001, 87:362-369quiz 370, 423.

 7.  Garcia-Lloret M; McGhee S; Chatila TA: Immunoglubolin replacement therapy in children. Immunol Allergy Clin North Am. 2008; 28(4): 833-49, ix( ISSN:0889-8561).     

8. Levy, J; Espanol-Boren, T; Thomas, C, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr. 1997;131:47–54.

 9. Wang, WC; Cordoba, J; Infante, AJ; Conley, ME. Successful treatment of neutropenia in the hyper-immunoglobulin M syndrome with granulocyte colony-stimulating factor. Am J Ped Hemat/Oncol. 1994;16:160–3.

 10. Thomas, C; De Saint Basile, G; LeDeist, F, et al. Brief Report: correction of X-linked syndrome by allogeneic bone marrow transplantation. N Engl J Med. 1995;333:426–9.