An uncommon complication of a common diseaseInter-hospital Geriatric Meeting

Speaker: Dr. Chan FeiSupervisor: Dr. James Luk

29th Oct 2010

History• F/78, Madam Ng

• Lives with son• Non-smoker, non-drinker

• Community walker• Independent activity of daily living

• No known drug allergy

History

• History of trochanteric fracture of left femur with dynamic hip screw (DHS) done in May 2010

• Walked with quadripod on discharge

Chief complaint

• Admitted on 30 Aug 2010

• Reduced oral intake for one week• Refused food as very poor appetite,

only took some milk• Subjective weight loss

• No dysphagia / pain on swallowing• No vomiting/diarrhoea/abdominal

pain

Chief complaint

• Progressive deteriorated general condition since discharged fromorthopaedic ward, worsening of mobility and became chair-bound

• No limb numbness / weakness• No slurring of speech

• No headache• No fall

Physical examination

• BP 162/98 mmHg, Pulse 92 bpm• SaO2 97% on room air, Temp. 36.5C• Pallor +ve, no Jaundice/cyanosis• thin and mild dehydrated

• Chest , CVS , abdominal exam unremarkable• No cervical/axillary/groin lymphadenopathy• Breast exam normal

• Neurology exam showed generalized power 4+/5 except Lt hip , power 4-/5 as limited by pain

• otherwise normal reflexes and sensation• Cerebellar signs /Cranial nerves were normal• There was mild left hip pain on both active and passive

movement• Lt hip wound healing well with no swelling

Progress

• Clarify history of patient’s son and performed comprehensive geriatric assessment

• Madam Ng had progressive worsening of short term memory for more than one year with relative preservation of long term memory

• Before admission, her basic ADL already quite dependent with occasional disorientation and irrelevant speech

• No depressed mood

• Consulted orthopaedic team:1. XR left hip showed DHS in-situ with good alignment 2. FU 2 months after discharge with XR left hip on arrival3. Continue weight bearing exercise

Progress

• Baseline complete blood count, renal and liver function test

• Dementia work up ( TFT, VDRL, vit B12, folate and CT brain)

• CXR• Urine for microscopy and culture• Tumor markers

Investigations: ( day 1)

• Saved sputum for culture, AFB smear/culture and cytology

• Booked CT thorax with contrast and planned to discuss with relatives for bronchoscopy

Investigations ( complete blood picture)

Admission date

Investigations ( renal and liver function test)

Investigations ( clotting profile)

Progress ( Temperature and BP chart)

Progress: other investigations

• ESR 96mm/hr, LDH elevated

• Normal TFT, cortisol, vitamin B12 level

• RBC folate 95microgram/L, started on folatereplacement

• Blood smear: no fragmented red cells• Haptoglobin: normal

• CEA /AFP/Ca 15.3 normal• ANA, ANCA, anti-ENA unremarkable

• SIEP: monoclonal band +ve, with elevated IgA and IgG, normal IgM

Bone marrow aspiration examination report

Progress

• Started on intravenous zinacef 750mg Q8H

Summary of problems:

1. Pancytopenia2. Derranged clotting3. PUO4. Severe anorexia5. Significant deconditioning6. Monoclonal Gammopathy of

undertermined significance

Further workup:• Blood culture, urine culture , sputum culture and

sputum for AFB smear all negative

• Typhoid titre negative x2• Brucella titre negative x2• Weil-Felix titre negative x2• Burkholderia pseuomallei (melioidosis) AB titre

negative x2

• Parvovirus IgM negative• CMV pp65 negative• Monospot test negative• HIV ab, HBsAg/anti-HBS all negative

• Lupus anticoagulant, anti-cardiolipin ab and coagulation factor inhibitor screening negative

Progress

11/09/10 to 21/09/10

p.o.Doxycycline 500mg BD

11/09/10 to 21/09/10

i.v.Meropenam 1g Q12H

07/09/10 to 09/09/10

i.v.Rocephin 1g Q24H

31/08/10 to 06/0910

i.v.Zinacef 750mg Q8H

Progress• Hb 8.3g/dL, Neutrophil 1.2x10^9/L

• Platelet count 37x 10^9/L

• ALP 321U/L, AST 131 U/L, GGT 216U/L, Bilirubin 27umol/L

Progress

• Still on and off fever

• Worsening of pancytopenia• Developed derranged liver function

test• Ultrasound liver unremarkable• Further derranged clotting profile

• Remained poor oral intake and need temporary parenteral nutrition

Progress

The epidemiology of hyperferritinaemia

• Review 19 583 Iron profile measurements in a teaching hospital in Newcastle (UK)

• Used ferritin level >=1500microg/L (3370pmol/L, 7x of upper limit) as cutoff

• 199 patients identified

• 81 patients were identified as having a single cause for raised ferritin level

The epidemiology of hyperferritinaemia

Among these 81 patients1. 29.6% due to alcoholic liver disease2. 24.7% due to renal failure3. 9.8% due to other chronic liver disease4. 7.4% due to haematological disease or

repeated transfusions5. 6.2% due hereditary haemochromatosis6. 6.2% due to neoplasia7. 6.2% due to autoimmune disease and

inflammatory disorders

Cause of hyperferritinaemia in our patient

• Non-alcohol drinker• Normal renal function• Only received 2 unit of packed

cells transfusion

• Search through the literature, ferritin level >33000pmol/L essentially not found in patients with infectious disease alone

Cause of hyperferritinaemia in our patient: differentals

• ? Haemachromatosis

• ? Autoimmune disease, mainly adult still’s disease, systemic lupus erythematosus

• ? Haemophagocytic symdrome

Haemophagocytic syndorme(haemophagocytic lymphohistiocytosis)

• Haemophagocytosis : Dysregulatedproliferation of macrophages engulfing platelets, erythrocytes, leucocytes and their haematopoietic precursors

• Haemophagocytic syndrome is a disorder characterised by fevers, hepatosplenomegaly,cytopenias, and hyperferritinaemia and the pathological finding of haemophagocytosis in bone marrow and other tissues

Haemophagocytic syndorme

• Primary or familial haemophagocytic syndromeusually has a genetic aetiology

• Secondary haemophagocytic syndromeassociated with malignancy, autoimmune disease, or infection.

• First described in 1939

• 40 years later, understood that it was the inappropriate immune response during infection/autoimmune disease and leading to uncontrolled proliferation of benign histiocytes with haemophagocytosis

Immunopathological mechanisms

•

Trigger e.g. TB/virusTh1 cell and

CD8 lymphocytes(produce IFN-, IL-2 )

NK Cell(produce IFN-γ, TNF- αααα ,

Macrophage-CSF)

Macrophage(produce IL-6, IL-1, IL-8,TNF- α, IL-12)

Pathophysiology

• Impaired or absent function of NK cells and cytotoxicT cells is the hallmark of the disease.

• The cytotoxic activity of NK cells and of CD8+ T-cell lymphocytes is mediated by the release of cytolyticgranules (containing large amounts of perforin, granzymes, and other proteases) to kill the infected cells

• In study familial haemophagocytic syndrome, it was found that mutaion of genetic loci related to the activity of perforin and granzyme granule have been associated with genetic hemophagocytic syndrome

Pathophysiology

• Cytokine storm cause severe anorexia and systemic symptoms

• Cytopenia results from both hemophagocytosis in the bone marrow and depression of hematopoiesisby cytokines

• Serum ferritin elevation is the rule, the most likely mechanism being IL-1β elevation. Serum ferritinlevels may correlate with disease activity and outcome under treatment.

• Hypertriglyceridemia is an extremely common finding that is due to lipoprotein lipase inhibition by TNF-α

Pathophysiology

• Coagulation disorders are common. The most common pattern is fibrinogen deficiency due to liver dysfunction and, above all, plasminogen and factor-X activation by IL-1β.

• There was also evidence that fibrinogen was engulfed by the activated macrophages.

• Liver dysfunction (cytolysis and cholestasis) is frequently seen. IFN-γ contributes to the development of cholestasis and apoptosis.

Clinical features

• Acute onset with high-grade fever

• Rapid weight loss

• Macrophage and T-lymphocyte proliferation and activation may present with peripheral lymphadenopathy (35% of patients) and as enlargement of the liver and spleen (50% of patients)

• Clotting disorders may lead to bleeding, and liver involvement may manifest as jaundice and portal hypertension.

• Pulmonary infiltrates are found in 20–30% of patients, Skin abnormalities are noted in 20% of patients with the most common patterns being purpura and erythema.

• Of central nervous system manifestations, encephalopathy, meningitis, and seizures are the most commonly reported

• Patient usually died of multi-organ failure.

Table 1 HLH 2004 protocol – The diagnosis of HLH can be established by fulfilling five of the eight criteria

1. Fever (> 7 days).2. Splenomegaly.3. Bicytopenia without marrow hypoplasia including

(Hb < 9 g/dL, platelet count < 100 X 10^9/L, neutrophil < 1.10 X 10^9/L.)

4. Hypertriglyceridemia (3.0 mmol/L, fasting value) and/ or hypofibrinogenemia (< 1.5 g/L).

5. Hyperferritinemia (>500 ug/L; 1125 pmol/L).6. Low/ absent natural killer cell activity.7. Increased soluble CD25 levels (> 2400 IU/ml).8. Histological criteria: Hemophagocytosis.

• Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic andtherapeutic guidelines for hemophagocytic lymphohistiocytosis.Pediatr Blood Cancer 2007; 48: 124–31.

Progress of our patient

1. Fever (T>38.5C)

2. pancytopenia, (Hb 8.3g/dL, Neutrophil 1.2x10^9/L, Platelet count 37x 10^9/L)

3. hyperferritinemia (>33000pmol/L)

4. hypofibrinogenemia (0.22g/L)

5. hemophagocytosis within the bone marrow

• A diagnosis of haemophagocytic syndrome was made.

Patient’s bone marrow sample showsphagocytic cells with engulfed platelets

Evidence of haemophagocytosison histological samples.

Secondary causes of haemophagocyticsyndrome

Therapeutic options

• Supportive care

1. Transfusing fibrinogen, plasma etc2. Identify underlying infection and treat accordingly

• Specific Measures for life threatening hyper-inflammation and excessive cytokines

1. Steriod + etoposide (target monocyte) (useful in patients without systemic disease found)

2. Corticosteroid therapy ( SLE, still’s disease)3. TNF-alpha antagonist ( Still’s disease)4. Chemotherapy (lymphoproliferative disease)5. IVIG (some success if used early in infection)6. Haematopoietic cell transplant ( for familial cases with gene

mutations)

Progress

• With the help of microbiology team, a special AFB blood culture on Lowenstein-Jensen medium was arranged

• Result came back 2 weeks later: Positive for acid fast bacilli

• Gallium scan also arranged for PUO

Gallium scan of madam Ng

Progess

Gallium scintiscan report:

1. Tracer uptake in left hip region can be due to previous operation. However, more intense focal uptake at sub-trochanteric region is noted, possibility of infective focus cannot be excluded

2. Mild left chest infection and right lymphadenopathy

3. Non-specific uptake in right side of back of unknown significance, ? Mild soft tissue inflammation

Chest X-ray on day 23 after admission showing the presence of small well defined nodules distributed over both lung fields

CT thorax showing the numerous tiny nodules distributed diffusely in both lungs with right side pleural effusions and right basal atelectasis

A 1.2 cm rim enhancing lesion within the right psoa smuscle suggestive of a micro-abscess (arrow); an irregular destructive lesion is noted over the left side of fifth lumbar vertebral body (arrow-head)

A rim enhancing collection measures 4.7 X 3.9 X 8 cm (transverse diameter, antero-posterior distance, circumference) is noted over the lateral aspect of left hip joint and left proximal femur without any evidence of intra-articular extension

Progress

• Bronchoscopy shwoed copious sputum over bilateral bronchial tree, slightly inflammed mucosa over entry to left bronchioles.

• Bronchoalveolar lavage showed a positive result of polymerase chain reaction (PCR) for Mycobacterium Tuberculosis but negative for detection of Pneumocystis jiroveci, Cytomegalovirus (CMV) and Herpes Simplex Virus (HSV).

Progress

• Subsequently blood culture, sputum and early morning urine culture all grew acid fast bacilli.

•• Anti-tuberculous treatment including

Isoniazid, Ethambutol and Parazinamide were started on day 36 after admission.

• Rifampicin was added on Day 49 after cytopenia resolved

Progress

• Ultrasound guided drainage of the abscess attempted but could only collect a few ml of blood stained fluid.

• Microbiological investigation reviewed negative gram smear, aerobic culture, anaerobic culture and TB PCR.

• Orthopedic surgeon was consulted on the left hip condition and L5 infective lesion.

• Suggested for continue anti-TB treatment and for serial monitoring as there was no focal neurology for the time being

Overall diagnosis:

Disseminated tuberculosis (lung, bone, urine, blood) with secondary haemophagocytic syndrome

Progress

• The patient remained afebrileafter commencement of treatment; cell count and clotting profiles gradually improved

• Lumber puncture also performed and showed no evidence TB meningitis

Complete blood count

Progress

• Patient’s appetite was gradually improving

• Transferred to TB and Chest Unit (GH)forfurther titration of anti-TB treatment as derranged liver function

• Suffered from severe de-conditioning

• Will review by geriatric team and consider takeover for rehabilitation later

Literature review• total 51 cases reported (search through PUBMED). Male to

female ratio is 1.22

• The average age of onset was 47.4 years old. 56% would have underlying disease that predispose to disseminated tuberculosis.

• Overall survival rate is 53%. (mortality of 47%)

• The mortality would be of 100% if no anti-tuberculous treatment were instituted.

• For those who received anti-tuberculous treatment (with or without immunotherapy), the survival is 66% (mortality of 34%).

• If only anti-tuberculous treatment is instituted, the survival is of 87.5%.

• If both anti-tuberculous and immunotherapy were prescribed, the survival is of 60%.

• If only immunotherapy was prescribed (only one case), the mortality is 100%.

Clinical features of patients with tuberculosis associated haemophagocytic syndrome

Clinical features of patients with tuberculosis associated haemophagocytic syndrome

Clinical features of patients with tuberculosis associated haemophagocytic syndrome

Clinical features of patients with tuberculosis associated haemophagocytic syndrome

Geriatric point of view

• Total 14 patients (27.5%) were over the age of 65 years old.

• Male to female ratio is 1:1.

• 93% has presented with disseminated tuberculosis

• 60% does not have underlying predisposing conditions.

• 40% has predisposing conditions including 2 with cancer and 4 patients with chronic renal failure

Asian and Hong Kong data

• There were 12 patients from the Asian countries.

• Male to female ratio is 1:1.

• 50% of the patients do not have underlying contributing factors to tuberculosis.

• Overall the mortality is 73%

• There were 3 patients previously reported in Hong Kong. All of them had underlying contributing factors, namely NPC, SLE and sacroidosis

• 2 of them received treatment and one of them did not.

• The mortality is 100%.

• Early diagnosis is essential for survival, consider the possibility of disseminated tuberculosis in elderly patient with hemophagocyticsyndrome

Thanks

Acknowledgement

• Dr. James Luk• Dr. Shea Y.F.• Dr. Jason So (Pathology)