2002 Jun - A Patient with TB “Exacerbation”
Dr BL Tai*, Dr CK Chan, Dr CM Tam, Tuberculosis and chest service, Department of health, Medical Department, Queen Elizabeth Hospital
Case History
Our patient was a twenty-five years old bar waitress. She was an ex-smoker. She had been sexually active and had multiple sex partners. She had been taking oral contraceptives for ten years. Her past health included childhood asthma and eczema that were in remission.
DAY 1
She was admitted to Queen Elizabeth Hospital on 20 June 2001 for cough with yellowish sputum and fever for ten days. There was no urinary symptom or any gastrointestinal upset. Her last menstrual period was in April 2001.
Physical examination revealed a high fever of 40 °C. A mobile lymph node of one centimeter in diameter was palpable in the left supraclavicular fossa. Her blood pressure was 98/70 mmHg and pulse was regular, at 130 per minute. No other positive physical sign was detected.
Investigation results were as follow:
CBP Hb = 7.2 g/dL, normochromic, normocytic WBC = 5.6 x 1O9/L (neutrophil = 5.1, lymphocyte = 0.3)
Platelet = 158 x 1O9/L
Reticulocyte count = 1.3%
ESR 135
LFT albumin = 23 g/L, globulin = 35 g/L, total bilirubin = 7 /lmol/L,ALP = 128 U/L,ALT= 42 U/L
RFT Na = 124 mmol/L, K = 3.2 mmol/L, urea = 3.6 mmol/L, creatinine = 60 /lmol/L
Spot sugar : 7.2 mmol/L
CRP : 274 mg/L
HbsAg : -ve
Anti HCV : -ve
ANF : - ve
ANCA : -ve
TSH : 1.3mIU/L
Pregnancy test: -ve
ECG : s inus tachycardia
CXR (Figure 1) showed fine mottling shadows in both lower zones.
DAY5
She had persistent fever and developed Type 1 respiratory failure despite having received intravenous Cefuroxime for five days. Repeated CXR showed deteriorating diffuse lung shadows (Figure 2). Clarithromycin and empirical anti-TB drugs including Isoniazid 300 mg QD, Rifampicin 450 mg QD, Ethambutol 1250 mg QD and Pyrazinamide 1500 mg QD were started. Sputum for AFB smear was positive and subsequent culture confirmed Mycobacterium tuberculosis with favourable sensitivity pattern. Fine needle aspiration of the left supraclavicular lymph node was performed and culture of the aspirate also showed Mycobacterium tuberculosis with favourable sensitivity pattern. Anti-HIV serology was positive, CD4 count was 32/mm3, CD8 count was 230/mm3 and HIV viral load was 139xlOOOcopies/ml.
Her clinical condition gradually improved. Her liver function, however, became mildly deranged, with an alkaline phosphatase level of 373 U/L and an alanine transaminase level of 101 U/L. Ultrasound of the hepatobiliary system was normal. The anti-TB regimen was changed to Streptomycin, Isoniazid, Ofloxacin and Ethambutol. Her liver function gradually improved.
WEEK-4
She was successfully discharged after four weeks' hospitalization. Prescriptions upon discharge were Isoniazid, Ethambutol, Ofloxacin and Septrin. Rifampicin, Azithromycin, Lamivudine and Stavudine were added four days later in out-patient clinic.
WEEK 6
Patient attended Chest Clinic for supervised anti-TB treatment. She presented with mild cough and was afebrile. Her liver function further improved. CXR showed improving lung shadows (Figure 3).
WEEK8
Patient was readmitted to Queen Elizabeth Hospital for fever, chills and rigor for three days. She also complained of generalized colicky abdominal pain and watery diarrhea. She claimed to have good drug compliance with both the anti-TB drugs and antiretroviral therapy. Physical examination did not reveal any significant abnormality except high.
Investigations results:
CBP : Hb= 9.7 g/dL, WBC = 8.4 x 1O9/L, lymphocyte count = 1.0 x 109/L, platelet count = 174 x 109/L
RFT Na = 127mmollL, K = 3.2 mmollL, urea = 3.7 mmollL, creatinine = 49 f.lmollL
LFT albumin = 30 glL, globulin = 34 glL, bilirubin = 21 mmollL, ALP = 144 UIL, ALT= 36 U/L
Amylase 45 uIL
Spot sugar 4.8 mmol/L
ABG on room air: pH = 7.48, pCO2= 2.9 kPa, pO2= 7.0 kPa, HCO3 = 16 mmol/L, BE = -5.3, SaO2= 90 %
CXR showed worsening diffuse lung shadows (Figure 4)
Septic work up :
Stool x culture, ova and cyst -ve
Stool xAFB smear and cryptosporidium -ve
MSU x RIM culture -ve
MSU x AFB smear and culture -ve
Blood culture -ve
Blood x CMV -ve
Sputum x culture showed Candida
Sputum x AFB smear and culture, PCP -ve
Flexible bronchoscopy was performed and did not show any endobronchial lesion. Bronchial aspirate for microscopy, culture, AFB, cytology, fungus, CMV,PCP showed negative results.
Treatment with Isoniazid, Ofloxacin, Ethambutol and antiretroviral drugs was continued during her second hospitalization. On day 3, high dose Septrin, Clarithromycin and oral prednisolone 40 mg BD were started. On day 4, Sulperazone and Cloxacillin were initiated. On day 6, Sulperazone was changed to Meropenem. Her fever gradually came down and her blood gas improved. Oral steroid was gradually tailed down. She was eventually discharged with Isoniazid, Ofloxacin, Ethambutol, Septrin, Azithromycin , Stavudine, Lamivudine, Prednisolone 5 mg QD. Rifampicin and Stocrin were added in out- patient clinic. Her serial CXR's showed gradual resolution of lung shadows (Figure 5).
Case Summary
Our patient had human immunodeficiency virus infection complicated by active tuberculosis involving the lungs and cervical lymph node. She showed initially satisfactory clinical and radiological response to anti-tuberculous treatment. After about seven weeks' of anti-tuberculous treatment and three weeks' of antiretroviral therapy, her clinical and radiological state deteriorated. Extensive septic work up did not show any other focus of infection. While continuing anti-tuberculous drugs, antiretroviral therapy, and commencing broad-spectrum antibiotics, high dose Septrin and high dose steroid, she gradually improved.
Discussion
The differential diagnoses which may account for the fluctuating clinical course in this patient include resistant strain of Mycobacterium tuberculosis, poor drug compliance, malabsorption, opportunistic infections other than tuberculosis and immune reconstitution syndrome.
Repeated sputum culture showed sensitive strain of tuberculosis and her compliance with both the anti-tuberculous and antiretroviral drugs were good. Malabsorption was unlikely as her body weight was increasing and serum albumin and haemoglobin level were rising. Negative results on extensive septic work up make the possibility of other infections unlikely. After ruling out these four possibilities, immune reconstitution syndrome was probably the most likely diagnosis.
The introduction of potent antiretroviral drugs leads to a substantial reduction in morbidity and mortality in HIV patient. This is mediated by a decrease in viral load, increase in CD4 count and restoration of cell mediated immune function. However, there are many drawbacks with antiretroviral therapy including side effects such as hyperlipidaemia, hyperglycaemia, lactic acidosis, lipodystrophy, as well as interactions with other drugs. In addition, paradoxical reactions had increasingly been reported in patients with tuberculosis, Mycobacterium avium complex infection, cytomegalovirus infection, hepatitis B, hepatitis C and herpes
zoster.
Transient worsening of tuberculosis symptoms after anti-tuberculosis therapy has been reported in immunocompetent patients. This can manifest as worsening lymphadenopathy, pulmonary infiltrates, pleural disease, cerebral tuberculomas and acute respiratory distress syndrome.
This hypersensitivity response was provoked by an improved immune function and the release of mycobacterial antigens from the destroyed Mycobacterium tuberculosis. In the era of highly active anti-retroviral therapy for HIV infection, paradoxical reactions have been increasingly reported. The temporal association of the paradoxical reactions after initiation of the antiretroviral therapy suggests that clinical manifestations are attributable to restoration of immunity to mycobacterial antigens.
In a prospective study [1], Narita and co-worker defined paradoxical reactions as new fever, worsening or emergence of lymphadenopathy, pulmonary infiltrates or, pleural effusion, or worsening of other tuberculous lesions. They noted that HIV-infected patients treated with antituberculous and antiretroviral therapy had a higher incidence of paradoxical reactions (12/33 or 36%) compared with HIV negative patients receiving anti-tuberculous treatment (1/55 or 2%) or HIV-infected patients receiving anti-tuberculous treatment but not antiretroviral therapy (2/28 or 7%). The mean time to the onset of paradoxical worsening was 15 +/- 11 days after initiating antiretroviral therapy. Other authors, however, had reported a much lower rate of paradoxical reactions among HIV-infected patients being treated with for tuberculosis, presumably due to differences in populations. [2]
Risk factors of the paradoxical reactions included those with advanced HIV infection, greater HIV RNA suppression after initiating antiretroviral therapy [1]and those receiving antiretroviral therapy within the first two months of anti TB treatment [3]. Paradoxical reactions do not appear to be associated with specific classes of antiretroviral therapy.
The diagnosis of paradoxical reactions is often by exclusion: anti-TB drug resistance, drug reactions, malabsorption, poor drug compliance, other opportunistic infections should be considered.
The management of paradoxical reactions depends on the severity of the symptoms. Mild to moderate reactions can be managed conservatively or by non-steroidal anti-inflammatory agents. Severe reactions can be managed by corticosteroids after comprehensive efforts have been made to exclude alternative etiologies. The duration of corticosteroid therapy depends on the clinical symptoms[4] Discontinuationof antiretroviral therapy is seldom necessary.
The interactions between antiretroviral drugs and anti-tuberculous agents often cause trouble in the management of HIV-infected patients being treated for tuberculosis. Current antiretroviral regimens usually consist of combination of drugs from two or three different classes of drugs: nucleoside reverse transcriptase inhibitors eg zidovudine, lamivudine, stavudine; non-nucleoside reverse transcriptase inhibitors eg nevirapine, efavirenz, delavirdine; and protease inhibitor eg indinavir, nelfinavir, ritonavir [4]. Rifamycins are inducers of cytochrome P450-3A system in the intestinal wall and liver, resulting in decrease in the serum concentrations of protease inhibitors and non-nucleoside reversetranscriptase inhibitors which are metabolized by this enzyme system.
Rifamycins differ in potency as cytochrome P450-3A inducers, with rifampicin being the most potent and rifabutin being the least potent inducer. On the other hand, delavirdine and the protease inhibitors are potent inhibitors of cytochrome P450-3A, so increasing the serum concentrations of drugs metabolized by that enzyme system, rifabutin being one of the examples. To minimize the harmful effects of the drug interactions, physicians may consider: (I) deferring antiretroviral therapy until completion of anti-tuberculous treatment; (2) standard anti-tuberculous therapy with nucleoside reverse transcriptase inhibitors based anti-retroviral therapy; (3) standard anti-tuberculous therapy in which rifabutin at half the usual dose is substituted for rifampicin. [5].
As newer and more potent antiretroviral regimens are expected to come into the market, more complex drug-drug interactions and additional immune-mediated disorders will probably be observed. Collaboration between HIV care providers and respiratory physicians is essential in improving the success rate in treatment of tuberculosis and suppression of HIV replication.
References
- Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998; 158:157-161.
- Wendel KA, Alwood KS, Gachuhi R, Chaisson RE, Bishai WR, Sterling TR. Paradoxical worsening of tuberculosis in HIV-infected persons. Chest 2001; 120: 193-197.
- Navas E, Moreno L, Martin-Davila V, Dronda F, Perez-Elias MJ, Cobo 1. Tuberculosis reactivation in AIDS patients treated with highly active antiretroviral therapy [abstract]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco. 1999
- Burman WI, Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med 2001; 164:7-12.
- Mayaud C, Cadranel 1. AIDS and the lung in a changing world. Thorax 2001; 56:423-426.
