2013 July - Devoured beyond savage
Drs Cheung Wai SZE, Yiu Ping NG and Kit Man SIN
Department of Medicine & Geriatrics, Tuen Mun Hospital & Pok Oi Hospital
History
A 35 years old lady presented to AED with severe sore throat.
She presented with severe sore throat for 2 weeks. There was associated on and of fever which did not respond to Clarithromycin prescribed by a general practitioner. There was odynophagia resulting in poor oral intake. There was no history of foreign boy ingestion.
She was a domestic helper from Indonesia and worked in Hong Kong for 8 years. She enjoyed past health. There was no significant family history, drug history, recent travel history or contact history.
The patient was dehydrated and cachexic. Tonsils were enlarged and tender. There were two palpable right enlarged cervical lymph nodes, each of which of 2 cm in size. Breath sounds were normal. There was splenomegaly. The WBC was 2.6 x 109/L with both low in neutrophil and lymphocyte. Serum ALT was 43 IU/L slightly elevated. Serum LDH was elevated at 526 IU/L. Hepatitis B and C markers were negative. Prothrombin time and activated partial thromboplastin time were prolonged. Serum ferritin and triglyceride were also elevated. CRP was 5.3 mg/L and ESR was 58 mm/h. CXR was clear.
The patient remained in persistent fever despite broad spectrum antibiotics with Augmentin, Zithromax and later Tazocin. Sputum, midstream urine, blood culture, throat swab did not reveal any micro-organisms. Nasopharyngeal swab was negative with influenza. Sputum and early morning urine AFB were negative. Monospot test was negative. Anti-HIV was negative.
Right cervical lymph node FNAC was negative for bacterial and AFB culture. Cytology showed lymphocytes admixed with a small number of medium-size lymphoid cells and histiocytes. There was no necrosis nor malignant cell. Features were suspicious of mycobacterial infection.
Right cervical lymph node biopsy was done and revealed mostly necrotic material. Adjacent viable area showed mixed lymphoid cells and nuclear debris but obvious granuloma or multinucleated giant cells were not seen. The lymphoid cells were mildly atypical and favored reactive atypia. ZN stains for AFB and PAS stain for fungi were negative. PCR for MTB complex DNA was positive.
The patient was diagnosed with tuberculosis and was put on isoniazid, rifampicin, pyrazinamide and ethambutol adjusted to her body weight since day 21 of admission.
CT neck, thorax and abdomen showed inflammatory changes at right lateral wall of the oropharynx probably with abscess formation, clusters of right enlarged cervical lymph nodes and mild splenomegaly.
Right tonsil biopsy was performed by ENT surgeon and histology showed fragments of necrotic tissues with minimal viable tissue. There was no definite evidence of granulomatous inflammation or malignancy. Ziehl-Neelsen stain for acid-fast bacilli and Grocott stain for fungus were negative.
Because the patient had increasing trend of transaminases with ALT more than 200 IU/L persistently, the anti-TB treatment regimen was switched to streptomycin, ethambutol and levofloxacin.
On day 56 the patient deteriorated with low fibrinogen, markedly prolonged prothrombin time, activated partial thromboplastin time, LDH and ferritin.
Bone marrow smear and trephine biopsy confirmed haemophagocytosis which was readily seen with macrophages engulfing red cells, white cells and platelets. Bone marrow smear and culture did not reveal any AFB.
Because of haemophagocytic syndrome, extensive workup was made to rule out other potential underlying cause. Serum viral titres of influenza, parainfluenza, adenovirus, RSV, CMV, EBV, HIV, HBV and HCV were all negative. Aspergillus antigen EIA and antibody were negative, as well as cryptococcal antigen. Coccidioides, Blastomyces, Histoplasma, Penicillium marneffei serum antibody were all negative.
A repeated contrast CT scan from neck to pelvis showed massive ascitic fluid with slightly dense fluid, together with smoothly thickened enhancing peritoneum and enlarged intra-abdominal lymph nodes compatible with tuberculous peritonitis. There was hepato-splenomegaly. No occult malignancy was detected.
A diagnosis of haemophagocytosis secondary to tuberculosis was made. Intravenous dexamethasone and IVIG was initiated on day 60.
The patient however deteriorated and developed ARDS, shock and multiorgan failure and succumbed.
Discussion
Hemophagocytic syndrome, also named hemophagocytic lymphohistiocytosis (HLH), is a rare but potentially fatal hyperinflammatory syndrome. It is caused by severe hypercytokinemia due to a highly stimulated but ineffective immune process.
It can be classified into primary HLH and secondary HLH. For primary HLH, it is more commonly seen in children with a genetic predisposition (e.g., PRF1 mutation) Bone marrow transplant is required for cure of the disease.
For Secondary HLH, which can present at any age, is usually triggered by infections, malignancy and rheumatic disease. Among those cases associated with infection, viral infections (e.g. EBV infection) are more common, while bacterial infection and mycobacterium infection can also trigger HLH.
The pathogenesis of HLH is mainly due to immune dysregulation. Upon triggering to the immune system, the defective cytotoxic T cells and NK cells in HLH patient fail to kill the infected cells. This results in persistent activation and proliferation of macrophages and cytotoxic T cells and the massive release of the cytokines. (1)
Nearly all patients with HLH presented with prolonged fever, Splenomegaly and cytopenia. Other symptoms and signs include liver failure, lymphadenopathy and skin rash. Multi-organ failure, sepsis and profound bleeding will result in death. Diagnosis of HLH relies on clinical, laboratory, and histopathological findings. The diagnosis is made when at least five out of the following eight criteria is met: 1)Fever; 2)splenomegaly; 3) bicytopenia; 4) hypertriglyceridemia and/or hypofibrinogeemia; 5) hemopagocytosis; 6) low or absent natural killer (NK) cell activity; 7) hyperferritinemia 8) increased soluble CD 25 levels. (2)
Patients age older than 30 years old, the presence of DIC, increased ferritin level and increased B2-microglobulin are associated with poor prognosis and death. (3) Lymphoma associated HLH has higher mortality than those of infection associated HLH.
Tuberculosis is one of the triggering factors of HLH, though uncommon (about 3% of all cases). 83% of patients has extrapulmonary manifestion and make it difficult to be diagnosed. (4) In a case review of tuberculosis associated hemophagocytic syndrome, the mortality is 80% among local case. The overall mortality among all cases in literature is around 44%. All patients have fever and 98% have thrombocytopenia. (5) Patients may have subtle symptoms and signs of tuberculosis.
In general, management of HLH includes treating the triggering factor and HLH specific therapy. The Histiocyte Society establishes the use of HLH 2004 treatment protocol, which mainly use in patients with primary HLH, aiming at suppressing the hyperinflammation. (2) The protocol includes the use of dexamathasone, etoposide and cyclosporine A in both the initial phase and continuation phase of the treatment. In secondary HLH, treatment needs to be individualized. Treating the underlying infection alone is associated 60%-70% successful rate. The use of HLH 2004 treatment protocol should be considered when treating the triggering factors alone is not effective.
In TB associated HLH, there is no consensus in treatment of TB associated HLH. Most recommend early initiation of anti-tuberculosis treatment. In a review of 37 cases, 8 patients who did not receive any treatment died and 7 out of 9 patients recovered after receiving the anti-tuberculosis treatment. In the remaining patients, combination therapies were used, which included high dose steroid, splenectomy, IVIG and etoposide. (4)
Conclusion
Hemophagocytic syndrome is a rare disorder, and usually presents with non-specific symptoms. It causes multiple organ failure and even death despite treatment. HLH should be considered in tuberculosis patient with worsening symptoms.
Table 1. Diagnostic Criteria
Reference
- Rouphael N.G., Talati N.J., Vaughan C., et al. Infections associated with haemo-phagocytic syndrome. Lancet Infect Dis. 2007; 7:814-822
- Henter J.I., Horne A., Aricó M., et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lympho-histiocytosis. Pediatr Blood Cancer. 2007; 48:124-131.
- Kaito K., Kobayashi M., Katayama T., et al. Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases. Eur J Haematol. 1997: 59: 247-253
- Brastianos P.K., Swanson J., Torbenson M., et al. Tuberculosis-associated hemophagocytic syndrome. Lancet Infect. Dis. 2006; 6:447-454.
- Shea Y.F., Chan J.F., Kwok W.C., et al. Haemophagocytic lymphohistiocytosis: an uncommon clinical presentation of tuberculosis. Hong Kong Med J. 2012; 18:517-525.
