Common Variable Immunodeficiency – atypical presentation Sara Pereira da Silva, Susana Lopes da Silva SANTA MARIA HOSPITAL LISBONPORTUGAL

Common Variable Common Variable Immunodeficiency – atypical Immunodeficiency – atypical

presentationpresentation

Sara Pereira da Silva, Susana Lopes da Silva

SANTA MARIA HOSPITALSANTA MARIA HOSPITALLISBONLISBON

PORTUGALPORTUGAL

Case reportCase report

63 years old 63 years old Caucasian Caucasian Woman Woman

Referred for Referred for

hypogammaglobulinemiahypogammaglobulinemia

– 29 years old - Left supraclavicular lymphadenomegaly29 years old - Left supraclavicular lymphadenomegaly Histological examination – inconclusive (sarcoidosis?/tuberculosis?)Histological examination – inconclusive (sarcoidosis?/tuberculosis?)

Treatment with antituberculous agents during 2 yearsTreatment with antituberculous agents during 2 years

– 30 years old – allergic rhinosinusitis30 years old – allergic rhinosinusitis grass-polen sensitizationgrass-polen sensitization topical nasal corticosteroids and/or oral anti-Htopical nasal corticosteroids and/or oral anti-H11 < 1 episode/year< 1 episode/year


-- 33 years old33 years old – easy bruising and petechial rash – easy bruising and petechial rash THROMBOCYTOPENIA

DIAG: IMMUNE THROMBOCYTOPENIC PURPURA

splenomegalysplenomegaly bone marrow aspiration and biopsy – normalbone marrow aspiration and biopsy – normal

continued prednisolone, intermitently untill 39 year oldcontinued prednisolone, intermitently untill 39 year old since 44 – normal and stable platelet countsince 44 – normal and stable platelet count

treatment with prednisolone (dose?) during 2 yearstreatment with prednisolone (dose?) during 2 years refused splenectomyrefused splenectomy


Referred to PneumologyReferred to Pneumology

- pre-surgery evaluation- pre-surgery evaluation

Chest Radiography:Reticulonodular opacities

- 62 years old62 years old – episode of acute rhinosinusitis – episode of acute rhinosinusitis ENT evaluation ENT evaluation

- proposal for sinus surgery- proposal for sinus surgery


Reticular pattern with multiple, diffuse nodules and patchy ground glass opacification in both lungs

PneumologyPneumology

Chest CTChest CT


Pulmonary Function TestPulmonary Function TestDiscrete restrictive pattern (TLC – 83,2%)

Reduced diffusing capacity for carbon monoxide (DLco - 58%), but normal when adjusted for lung volume (DL,co/VA – 87,3%)


• Cell count

• Macrophages – 68% (74-98)

• Lymphocytes – 23% (8-16)

• Neutrophils – 9% (0-1,2)

• CD4 - 66% (37-53)

• CD8 - 26% (17-31)

• CD4/CD8 – 2,5 (2)

Flexible broncoscopyFlexible broncoscopyEndobronchial generalized inflammatory signsEndobronchial generalized inflammatory signs

Bronchoalveolar lavage (BAL)Bronchoalveolar lavage (BAL)• no infection or malignancy



““Interstitial inflammation and diffuse lymphoid infiltration with aggregates Interstitial inflammation and diffuse lymphoid infiltration with aggregates and lymphoid follicles, some with germinal centres”and lymphoid follicles, some with germinal centres”

Transbronchial BiopsyTransbronchial Biopsy

Open Lung BiopsyOpen Lung Biopsy““Dense interstitial lymphoid infiltrate with Dense interstitial lymphoid infiltrate with aareas of interstitial fibrosis and

lymphoid follicles. Alveolar septa extensively infiltrated, some with collapse of the air space.”

A specific diagnosis was not possible


Diagnosis ???Diagnosis ???

ORAL STEROIDSORAL STEROIDS

(45 mg deflazacort/day – 3 (45 mg deflazacort/day – 3 months)months)


during the investigation…during the investigation…

complaining of complaining of progressive fatigue progressive fatigue


63 years old – evaluation after 1 year of steroids treatment63 years old – evaluation after 1 year of steroids treatment


– considerable clinical improvementconsiderable clinical improvement

Clear regression of infiltrates and nodulesClear regression of infiltrates and nodulesDiscrete reticular pattern Discrete reticular pattern Multiple traction bronchiectasisMultiple traction bronchiectasis

- Pulmonary Function TestDiscrete restrictive pattern (TLC – 87,9%)Diffusing capacity for carbon monoxide - not performed


– Chest CTChest CT





– Laboratory evaluation:Laboratory evaluation: Haemoglobin: 16,2g/dlHaemoglobin: 16,2g/dl Leucocyts: 6 100/mmLeucocyts: 6 100/mm33 (N - 64,4%, E – 1,4%, B – 0,4%, L – 22,8%, (N - 64,4%, E – 1,4%, B – 0,4%, L – 22,8%,

M – 11,1%)M – 11,1%) Platelets: 217 000/mmPlatelets: 217 000/mm33

Serum protein electrophoresis – Serum protein electrophoresis – – 2,2% - 0,1 g/dL – 2,2% - 0,1 g/dL

IgA – 12 mg/dLIgA – 12 mg/dL (70-400) IgG – 106IgG – 106 mg/dL mg/dL (700-1600) IgM – 44 mg/dL IgM – 44 mg/dL (40-360)

bone marrow aspiration and biopsy – normalbone marrow aspiration and biopsy – normal


Referred to Primary Immuno Referred to Primary Immuno DeficiencyDeficiency


NO HISTORY ofNO HISTORY of Frequent or severe infectionsFrequent or severe infections Gastrointestinal diseases Gastrointestinal diseases Recurrent inflammatory arthritisRecurrent inflammatory arthritis

DENIEDDENIED

PIDPIDCase reportCase report

Fatigue, dyspnoea or cough Fatigue, dyspnoea or cough Recent weight loss or oedemaRecent weight loss or oedema

Past HistoryPast History– 62 years old - laparoscopic cholecistectomy 62 years old - laparoscopic cholecistectomy – No smoking habitsNo smoking habits– 6 pregnancies, 4 deliverys 6 pregnancies, 4 deliverys

Family HistoryFamily History Sister – Sister – Rheumatoid ArthritisRheumatoid ArthritisSister – Sister – Arthritis, not characterizedArthritis, not characterizedSister – Thyroid disease, submitted to surgerySister – Thyroid disease, submitted to surgery

Descendents - 2 Descendents - 2 ♀♀ and 2 and 2 ♂♂

♀ ♀ 34 years old – frequent diarrhea and uveitis34 years old – frequent diarrhea and uveitis

Case reportCase reportPIDPID

Physical ExaminationPhysical Examination

BMI =19BMI =19 (height – 161 cm, weight – 50 kg)(height – 161 cm, weight – 50 kg)

Splenomegaly, slightly painful at palpationSplenomegaly, slightly painful at palpation

Laboratory evaluationLaboratory evaluation

18/06/199818/06/199856 years old56 years old

20/04/200220/04/200260 years 60 years

oldold

30/06/200430/06/200462 years 62 years

oldold

20/10/20020/10/20055

63 years 63 years oldold

Hb Hb (g/dL)(g/dL)

13,713,7 13,313,3 13,713,7 16,216,2

Leuc Leuc (/mm3)(/mm3)

3 5003 500 3 3003 300 4 9004 900 6 1006 100

N N (%)(%)

5151 6666 5757 61,961,9

E E (%)(%)

66 22 7,87,8 1,51,5

B B (%)(%)

00 00 0,20,2 0,20,2

L L (%)(%)

3535 2323 26,226,2 25,225,2

M M (%)(%)

88 99 8,88,8 11,211,2

Plat Plat (/mm3)(/mm3)

146 000146 000 141 000141 000 163 000163 000 217 000217 000

Total ProteinsTotal Proteins (g/L)(g/L)

6565 5959 6060 6464

Albumin Albumin (g/L)(g/L)

4646 3737 38,638,6 68,4%68,4%

αα1/1/αα22 2,1%/10%2,1%/10% 8,9%/13%8,9%/13% 0,44/0,950,44/0,95 3,2%/14%3,2%/14%

ββ 10,8%10,8% 9,2%9,2% 0,450,45 12,2%12,2%

(%/g/dL)(%/g/dL)

5,0% - 0,335,0% - 0,33 6,2% - 0,376,2% - 0,37 4,2% - 0,254,2% - 0,25 2,2% - 2,2% - 0,100,10

After 1 year of

steroids treatment

Before steroids

NR: 10 - 19% / 0,6 – 1,6g/dL

18/06/199818/06/199856 years old56 years old

20/04/200220/04/200260 years 60 years

oldold

30/06/200430/06/200462 years 62 years

oldold

20/10/20020/10/20055

63 years 63 years oldold

27/04/200627/04/200663 years 63 years

oldold

Hb Hb (g/dL)(g/dL)

13,713,7 13,313,3 13,713,7 16,216,2 14,614,6

Leuc Leuc (/mm3)(/mm3)

3 5003 500 3 3003 300 4 9004 900 6 1006 100 6 6006 600

N N (%)(%)

5151 6666 5757 61,961,9 71,671,6

E E (%)(%)

66 22 7,87,8 1,51,5 0,50,5

B B (%)(%)

00 00 0,20,2 0,20,2 0,20,2

L L (%)(%)

3535 2323 26,226,2 25,225,2 17,317,3

M M (%)(%)

88 99 8,88,8 11,211,2 10,410,4

Platelets Platelets (/mm3)(/mm3)

146 000146 000 141 000141 000 163 000163 000 217 000217 000 171 000171 000

Total Protein (g/LTotal Protein (g/L)) 6565 5959 6060 6464 6262

Albumin (g/L)Albumin (g/L) 4646 3737 38,638,6 68,4%68,4% 37,937,9

αα1/1/αα22 2,1%/10%2,1%/10% 8,9%/13%8,9%/13% 0,44/0,950,44/0,95 3,2%/14%3,2%/14% 8,2%/16,1%8,2%/16,1%

ββ 10,8%10,8% 9,2%9,2% 0,450,45 12,2%12,2% 11,1%11,1%

(%/g/dL)(%/g/dL)

5,0% - 0,335,0% - 0,33 6,2% - 0,376,2% - 0,37 4,2% - 0,254,2% - 0,25 2,2% - 2,2% - 0,100,10

3,4% - 3,4% - 0,210,21

6 month without steroids

NR: 10 - 19% / 0,6 – 1,6g/dL

Before steroids

After 1 year of steroids treatment

LaboratoryLaboratory evaluationevaluation

– Ig G -160 mg/dL Ig G -160 mg/dL (700-1600)(700-1600)

Ig GIg G11 – 137 mg/dL – 137 mg/dL (700-1600)(700-1600) Ig GIg G2 2 – 9 mg/dL– 9 mg/dL (490-1140)(490-1140) Ig GIg G3 3 – 27 mg/dL – 27 mg/dL (20-110)(20-110) Ig GIg G4 4 – 0 mg/dL– 0 mg/dL (8-140)(8-140)

– Ig A - 8 mg/dL Ig A - 8 mg/dL (70-400)(70-400)

– Ig M – 32 mg/dL Ig M – 32 mg/dL (40-360)(40-360)

– Total Ig E << 3,9 U/mLTotal Ig E << 3,9 U/mL

- 62- 62- 37,9- 37,9- - 8,2 /16,18,2 /16,1- 11,1- 11,1- 3,4% - 0,21- 3,4% - 0,21

Total protein Total protein (g/L)(g/L)Albumin Albumin (g/L)(g/L)αα1/1/αα2 2 (%)(%)ΒΒ (%)(%)γγ (%/g/dL)(%/g/dL)

Serum protein electrophoresis

Immunoelectrophoresis – normal


Laboratory evaluationLaboratory evaluation

ββ22-microglobulin: 3,93 mg/L-microglobulin: 3,93 mg/L (0,8-(0,8-2,2)2,2)LDH: 453 U/LLDH: 453 U/L

ACE: 49 U/LACE: 49 U/L11-antitripsin: 36 UI/L-antitripsin: 36 UI/L

CRP: 0,29 mg/dLCRP: 0,29 mg/dLESR: 16 mmESR: 16 mm

renal and hepatic biochemistry - normalthyroid function - normal

NEGATIVE

AutoimmunityAutoimmunity– Antinuclear AbAntinuclear Ab– Anti-DS-DNA AbAnti-DS-DNA Ab– Anti-RO (SS-A) AbAnti-RO (SS-A) Ab– Anti-LA (SSB) AbAnti-LA (SSB) Ab– Anti-sm AbAnti-sm Ab– Anti-scl 70 AbAnti-scl 70 Ab– Anti-Jo 1 AbAnti-Jo 1 Ab– Antiribosome AbAntiribosome Ab– Anti RNP-Sm AbAnti RNP-Sm Ab– Anticentromere AbAnticentromere Ab

SerumSerum Immune-complexImmune-complex

Laboratory evaluationLaboratory evaluation 6 month without steroids

Cultural testCultural test– sputum sputum – fecesfeces– urineurine

VirologyVirology– HIV, HBV, HCVHIV, HBV, HCV

NEGATIVE

Ø

Skin prick test positive for:• lolium perene• parietaria officinalis, • parietaria judaica• tree polen mixtureSpecific IgE - Negative

Specific/vaccine antibodies production:Specific/vaccine antibodies production: anti – anti – H. influenzae H. influenzae Ab Ab - after vaccination- after vaccination

Very Low

NEGATIVE

Laboratory evaluationLaboratory evaluation 6 month without steroids

Lymphocytes ImmunophenotypeLymphocytes Immunophenotype CD3CD3+ + - 74,4% / 805,7 /- 74,4% / 805,7 /µL (p10)µL (p10) CD4CD4+ + - 39,5% / 427,7 /- 39,5% / 427,7 /µL (p5)µL (p5) CD8CD8+ + - 30,5% / 330,3 /- 30,5% / 330,3 /µL (p25)µL (p25) CD19CD19+ + - 6,7% / 72,6 /- 6,7% / 72,6 /µL (<p5)µL (<p5) CD3CD3- - CD56CD56+ + - 4,2% / 45,5 /- 4,2% / 45,5 /µL (<p5)µL (<p5)

B lymphocytes (B lymphocytes (GateGate at CD19 at CD19++))CD27CD27++IgDIgD++ 7% 7%CD27CD27++IgDIgD-- 5% 5%

Blood Type: B Rh+Blood Type: B Rh+ isohemagglutinin anti-Aisohemagglutinin anti-A (titre)(titre) - 1 - 1

Chest CT Chest CT

Traction bronchiectasis in peripheral areas of more intense fibrosisDiffuse interstitial infiltrates, in both lungs

Abdominal ultrasonographyAbdominal ultrasonography Splenomegaly (14,7 cm X 8,4 cm)Splenomegaly (14,7 cm X 8,4 cm)

Sinus CTSinus CTHyperthophic rhinitis Chronic bilateral maxillary sinusitis


PulmonaryPulmonary Function TestFunction TestDiffusing capacity for carbon monoxide - 72,1 %

CVIDCVID

– Lymphoid Interstitial Pneumonia Lymphoid Interstitial Pneumonia

– Chronic Allergic RhinosinusitisChronic Allergic Rhinosinusitis

– Immune Thrombocytopenic Purpura – Immune Thrombocytopenic Purpura – in remissionin remission

– SplenomegalySplenomegaly

DiagnosisDiagnosis

No significative infectionsNo significative infections

February/06 – February/06 – Herpes varicela-zoster Herpes varicela-zoster cutaneous cutaneous infectioninfection

No respiratory complaintsNo respiratory complaints

EvolutionEvolution

Evolution - TherapeuticsEvolution - Therapeutics

1 1 Postpone beginning immunoglobulin replacement Postpone beginning immunoglobulin replacement therapytherapy

2 2 worsening documented by chest CT worsening documented by chest CTpneumology decided to restart steroidspneumology decided to restart steroids, in , in

August/06:August/06: deflazacort – 21 mg/daydeflazacort – 21 mg/day budesonido – 400budesonido – 400g, 2 twice/dayg, 2 twice/day

November/06 to January/07– 4 episodes of acute rhinosinusitis, treated with antibioticsNovember/06 to January/07– 4 episodes of acute rhinosinusitis, treated with antibiotics

3 3 January/07 - Began intravenous immunoglobulin immunoglobulin replacement therapyreplacement therapy (400 mg/Kg)

Lymphocytic Intersticial Lymphocytic Intersticial Pneumonia (LIP)Pneumonia (LIP)

UncommunUncommun

1969 - Liebow and Carrington originally classified as an idiopathic 1969 - Liebow and Carrington originally classified as an idiopathic interstitial pneumonia interstitial pneumonia

Removed from that category - belongs within a Removed from that category - belongs within a spectrum of spectrum of pulmononary lymphoproliferative disorders pulmononary lymphoproliferative disorders

2002 – ATS/ERS consensus – classification of IIP 2002 – ATS/ERS consensus – classification of IIP – LIP included because of its clinical, radiographic and pathologic featuresLIP included because of its clinical, radiographic and pathologic features

Diffuse hyperplasia of bronchus-associated Diffuse hyperplasia of bronchus-associated lymphoid tissuelymphoid tissue

Microscopic dominant features Microscopic dominant features

diffuse, polyclonal lymphoid cell infiltrates diffuse, polyclonal lymphoid cell infiltrates surrounding surrounding airwaysairways and interstitium and interstitium

++ ++ ♀♀

55thth decade decade

Idiopathic?Idiopathic?

Infections (Infections (Pneumocystis jeruveci, Pneumocystis jeruveci, HBV, EBV)HBV, EBV)

Systemic diseasesSystemic diseases

– Autoimmune diseases (Autoimmune diseases (Sjogren,Sjogren, RA, SLE) RA, SLE)

– Immuno deficienciesImmuno deficiencies (HIV, (HIV, CVIDCVID))

Late complication of allogenic bone marrow transplantation Late complication of allogenic bone marrow transplantation

Association 1Association 1st st described in described in 1973, by Liebow e Carrington 1973, by Liebow e Carrington

++ T CD++ T CD44+ + cell infiltrationcell infiltration


80% - serum dysproteinemias80% - serum dysproteinemias

SymptomsSymptoms: progressive cough and dyspnea : progressive cough and dyspnea – VERY INSIDIOUSVERY INSIDIOUS

Great variability in clinical course Great variability in clinical course

Steroids are the mainstain of the therapySteroids are the mainstain of the therapy

– Response is unpredictableResponse is unpredictable– 50-60 % - stabilization or improvement50-60 % - stabilization or improvement

33 - 50% - die within 5 years33 - 50% - die within 5 years

5% transform to lymphoma5% transform to lymphoma


10% hypogammaglobulinemia10% hypogammaglobulinemia

Spontaneous resolutionSpontaneous resolution

Progressive respiratory failure and deathProgressive respiratory failure and death

PrednisonePrednisone

0,75 - 1 mg/Kg/day – 8 to 12 weeks0,75 - 1 mg/Kg/day – 8 to 12 weeks0,25 mg/Kg/day – 6 to 12 weeks0,25 mg/Kg/day – 6 to 12 weeks

ReferencesReferences

Notarangelo, L, Casanova,JL, Conley, ME,Chapel H, Fisher A, Puck J et al. Primary imunodeficiency diseases: An update from the International Union of Immunological Societies Primary Immunodeficiency diseases Classification Commitee Meeting in Budapest, 2005. J Allergy Clin Immunol 2006;117:883-96

Mouthon L, Berezne A, et al. Diagnostic des déficits immunitaires primitifs à l’âge adulte. Press Med 2006; 35:903-11

Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol 2004;114:415-21

Swigris JJ, Berry GJ, raffin TA, Kuscner WG. Lymphoid Interstitial Pneumonia – A Narrative Review. Chest 2002;122:2150-2164

American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopatic Interstitial Pneumonias. Am J Respir Crit Care Med 2002;165:277-304

North ME, Spickett GP, Webster ADB, Farrant J. Raised serum levels of CD8, CD25 and β2-microglobulin in common variable immunodeficiency. Clin.exp.Immunol. 1991; 86, 252-255

Davies CH, Juniper MC, Gray W, Gleeson FV, Chapel HM, Davies RJ. Lymphoid interstitial pneumonitis associated with common variable hypogammaglobulinaemia treated with cyclosporin A.Thorax 2000;55;88-90

Lynch DA, Travis, WD, Muller NL, Galvin JR, Hansell DM, Grenier PA, King TE. Idiopathic Interstitial Pneumonias: CT Features – Review Radiology 2005; 236:10-21

Swigris J,Berry G, Raffin G, Kushner W. Lymphoid Interstitial Pneumonia – A Narrative Review. CHEST 2002;122:2150-2164

Brandt D, Gershwin M. Common variable immune deficiency and autoimmunity. Autoimmunity Reviews 2006; 465-470

Bayry J, Hermine O, Webster D, Levy Y, Kaveri S. common variable immunodeficiency: the immune system in chaos. TRENDS in Mol Med 2005 (11) 8; 370-376

Documents

Common Variable Immunodeficiency – atypical presentation Sara Pereira da Silva, Susana Lopes da Silva SANTA MARIA HOSPITAL LISBONPORTUGAL