Clinical Meetings at RH Year 2008

2008 Jan 24 Clinical Meeting HOHH - A Man with Recurrent Chest Infection

Dr. Wong Wei Yin and Dr. Chan Kam Keung
Pulmonary and Palliative Care Unit, Haven of Hope Hospital

Case History

A 58 years old gentleman was an ex-smoker and nondrinker. He was married with one daughter. He had history of ocular myasthenia gravis diagnosed in 1994 and was put on mestinon 20mg b.d. and was in remission. Later, he was found to have invasive cortical thymoma (type B2) with pleural deposit. Thymectomy and left upper lobectomy was performed in 12/1994. However, he developed recurrence of thymoma over pleura diagnosed by open lung biopsy. He received palliative chemotherapy and radiotherapy and was completed in 10/2003.

He was admitted on 1/04, 2/04 and 4/04 for fever and increased purulent sputum. X-ray of chest showed right middle zone consolidation and sputum culture grew Haemophilus influenza. Clinical and radiological improved with antibiotics. Blood tests for HIV antibody, anti-nuclear antibody and rheumatoid factor were negative. Videofluoroscopic swallowing study showed no sign of aspiration. Bronchoscopy revealed no endobronchial lesion. CT thorax was done in 6/2004. It revealed pleura thickening over the left costophrenic recess corresponded to the site of pleural recurrence of the thymoma which was reduced in size. The dilated airways in both lungs were compatible with bronchiectasis. He was put on erythromycin 500mg b.d. since 8/2004 and the infective episodes decreased.

In 7/2005, he was admitted again for increased purulent sputum with sputum culture grew Pseudomonas aeruginosa. His condition was improved with Tazocin and was discharged. However, he was readmitted four days later for increased cough, yellow sputum and fever. CXR showed increased RUL and LMZ haziness. He was treated with Timentin and Gentamycin and improved. Sputum culture in that episode also grew Pseudomonas aeruginosa. He also complained of dyspepsia with OGD showed esophageal candidiasis and esophagitis. A course of fluconazole and proton pump inhibitor was given.

He was transferred to our hospital on 22/8/2005.Two days after completing the course of antibiotic, patient developed fever and increased purulent sputum again. He had no choking history and did not have abdominal pain, dysuria or arthralgia that suggestive of other sources of infection. He had no pet at home and no recent travel history. Reviewing his medication, he was taken Pyridostigmine bromide 20mg b.d., Lansoprazole 30mg daily, Senokot tab 15mg nocte and Combivent inhaler puff 2 q.i.d., Beclomethazone (250 mcg/dose) puff 2 q.i.d and Erythromycin 500mg b.d.. On physical examination, he had temperature of 38o C and crepitations over right lower zone of chest. He showed no dysphonia or fatiguability and no ptosis or diplopia. His power was full and no focal neurological sign demonstrated. The examination of cardiovascular and abdomen system were unremarkable. His CXR showed new right lung patchy infiltrates (Fig. 1)

His white cell count was 14.3x109 /L with 14.3% neutrophils and 32.3% lymphocytes. His hemoglobin level was 12.4g/dL. He had normal renal function and normal liver function except mildly elevated ALP of 184 U/L. HBsAg and HCV Ab were negative. His globulin level was 32 g/L. Fasting glucose was 4.5mmol/L. Repeated sputum culture grew Pseudomonas aeruginosa and was resistant to ciprofloxacin. Mid-stream urine and blood culture were negative. Fever was down and clinical and radiological (Fig.2) improved with Timentin and Gentamycin. However, patient developed recurrent episodes of fever and purulent sputum once antibiotics stopped. (Fig.3)


Fig.1 CXR before antibiotic Fig.2 CXR after antibiotic


Fig 3. Temperature Chart

Sputum for AFB smear and culture and Pneumocystic jiroveci were negative. Sputum for fungal culture grew Candida species which was accounted by the presence of oral candidiasis. Repeated HIV Ab testing was negative. Blood for atypical pneumonia titer and CMV pp65 were also negative. Repeated CT thorax showed collapse consolidation of left upper lobe and dilated bronchi in right lower lobe and left lower lobe suggestive of bronchiectasis (Fig.4). There were no mediastinal lymph nodes or pleural effusion. CT sinus revealed mucosal thickening and high density fluid was filling both maxillary sinuses bilaterally suggestive of sinusitis (Fig.5). He was seen by ENT and given Metronidazole and Ciprofloxacin for 10 days and no need for drainage. USG abdomen was unremarkable.


In view of the recurrent chest infection, investigation for the immunodeficiency was performed. The total IgG level was 14.34 g/L (normal range, 7 - 16), the IgA level was 0.08 g/L (normal range, 0.7 - 4) and IgM level was 0.1 g/L (normal range, 0.4 – 2.3). Peripheral blood lymphocyte subset profile by flow cytometry showed normal CD8 + count of 931/uL (normal range, 216 – 1100) with a decreased CD4+ count of 143 /uL (normal range, 376 – 1292). The ratio of CD4+ to CD8+ cells was 0.15 (normal range, 0.69 – 2.87) and there was absence of B cells. Serum protein electrophoresis showed IgG kappa monoclonal band of 8.8 g/L. Bone marrow aspiration revealed mild hypercellular marrow with plasma cells at 12%, consistent with monoclonal gammopathy of undetermined significance ( MGUS ). There were predominantly CD3 positive T cells with absence of B cells. He was diagnosed of Good’s syndrome (thymoma with immunodeficiency) associated with MGUS. The normal IgG level was accounted by the presence of monoclonal gammopathy. He was treated with IVIG, however patient continued to have recurrent chest infection required multiple courses of antibiotics. He developed chest infection in early March 2006. His condition deteriorated with antibiotic and IVIG and he developed septic shock and finally succumbed.

Discussion

Patients with recurrent or persistent sinopulmonary infections that fail to respond as expected to antibiotic therapy are commonly the presenting problem of primary or secondary immunodeficiency, which should be investigated thoroughly1. Primary immunodeficiency diseases are a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system. An update from the International Union of Immunological Societies Primary Immunodeficiency disease classification committee categorized primary immune deficiency diseases into eight groups 2. Thymoma and immunodeficiency is recognized as a primary immunodeficiency disease although the genetic defect is unclear and no familial cases have been reported. The disease is under the ‘Predominantly antibody deficiencies’ group. Common variable immunodeficiency disorders (CVID) and X-linked agammaglobulinemia (XLA) are also under this group. Thymoma and immunodeficiency was first recognized in 1954 by Dr. Robert Good and is commonly referred to as Good’s syndrome . There is no formal diagnostic criterion2. In patients with thymoma, the incidence of hypogammaglobulinaemia is 6-11%3. In one single institution, panhyogammaglobulinemia was found in 4 of 18 patients with pathological diagnosis of thymic tumour (22%)4. The principal immunological findings of Good’s syndrome are hypogammaglobulinaemia, few or absent B cells , an abnormal CD4+ : CD8+ T cell ratio, CD4 T cell lymphopenia, and impaired T cell mitogenic responses5. The cause and pathogenesis of this disorder are unknown. There are two possible pathogenic mechanisms. First explanation is that cytokines, possibly secreted by bone marrow stromal cells, may influence both thymic and B cell precursor growth and differentiation. A second explanation is related to T cell mediated immunosuppression5.

In a literature review of the infectious complications of Good’s syndrome, the mean age of the patients was 56 years (range, 29-75) at the time of the first manifestation ( infection, thymoma or hypogammaglobulinemia). The mean age of the patients was 62 years (range, 41-79) at the time when thymoma and hypogammaglobulinemia were both documentated6. The finding of immunodeficiency may precede or occur after the diagnosis of a thymoma. The histology of thymoma in Good’s syndrome is usually a spindle cell variant3,6. The most common cause of infection is recurrent sinopulmonary infection secondary to encapsulated organisms. This likely reflects the deficiency of humoral immunity, specifically the low serum levels of IgG. In contrast to patients with XLA and CVID, opportunistic infections associated with disorders of cell mediated immunity commonly occur in Good’s syndrome, in particular, CMV colitis and retinitis and mucocutaneous candida infections. CMV can occur in the presence of significantly greater T cell numbers than is seen in HIV infection. Opportunistic infection cause by herpes simplex, human herpesvirus 8, varicella zoster and Pneumocystic jiroveci pneumonia have also been described6. Diarrhea has been reported in almost 50% of patients. In most cases, no definite pathogens are identified; however, gastrointestinal pathogens, such as Giardia lamblia, non-typhoidal Salmonella, or cytomegalovirus are found occasionally6. Patients can have bacterial urinary tract and skin infections.

Anemia is present in over 50% of patients. Pure cell aplasia, aplastic anemia, hemolytic anaemia and pernicious anaemia have all been described. In one of the earliest review of this disorder pure red cell aplasia was noted in 35% of cases7 Thrombocytopenia and neurtopenia can also occur5. Monoclonal gammopathies have been described in Good’s syndrome8,9.

The mainstay of treatment for thymoma is removal or debulking of the tumour and the most important indicator of long term prognosis is completeness of tumour resection10. Unlike myasthenia gravis and pure red cell aplasia, removal of the thymoma or corticosteroid treatment do not reverse the immunological abnormalities3,5. The mortality rate was higher in patients with Good’s syndrome than patients with X-linked agammaglobulinemia or CVID11. In patients with Good’s syndrome, the long term outcome depends on infectious complications. Antibody deficiency requires immunoglobulin replacement treatment1,6. The IVIG infusions are usually given every 3 to 4 weeks at an initial dose of 0.4 to 0.6g/Kg. A dose must be individualized and titrated to achieve clinical effect in the patient being treated12.

References:

1. Internaltional Union of Immunological Societies. Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. Clin Exp Immunol 2000; 120: 225-31
2. Geha RS, Notarangelo LD, Casanova JL. Primary immunodeficiency diseases : An update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol 2007;120:776-94
3. Rosenow EC, Hurley BT. Disorders of the thymus. A review. Arch Intern Med 1984;144:763-72
4. Montella L, Masci AM, Merkabaoui G. B cell lymphopenia and hypogammaglobulinemia in thymoma patients. Ann Hematol 2003;82:343-47
5. Kelleher P, Misbah SA. What is Good’s syndrome ? Immnological abnormalities in patients with thymoma. J Clin Pathol 2003;56:12-6
6. Tarr PE, Sneller MC, Mechanic IJ. Infections in patients with immunodeficiency with thymoma. Report of 5 cases and review of the literature. Medicine 2001;80:123-33
7. Jeunet FS, Good RA. Thymoma, immunological deficiencies and haematological abnormalities. Birth Defects 1968;4:192-203
8. Sappi E, Eskala J, Veromaa T. Thymoma with immunodeficiency associated with myasthenia gravis and benign IgG gammopathy. Arch Intern Med 1985;145:1704-7
9. Jeandel C, Gastin I, Blain H. Thymoma with immunodeficiency associated with selective cobalamin malabsortion and benign IgM-K gammopathy. J Intern Med 1994;234:179-82
10. Riedel RF, Burfeind WR. Thymoma : Benign appearance, malignant potential. The Oncologist 2006;11:887-894
11. Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia : a survey of clinical manifestations and complication. Q J Med 1993;86:3-42
12. Orange JS, Hossny EM, Weiler CR. Use of intravenous immunoglobulin in human disease : A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 2006;117:S525-53