Incidental administration of corticosteroid can mask the diagnosis of tuberculosis.

To the Editor:

Miliary tuberculosis can present as severe sepsis, fulminant pneumonia, or acute respiratory distress syndrome, even in immunocompetent individuals. Corticosteroids are not uncommonly administered to patients with severe sepsis or asthma or to prevent reactions to contrast. We report 2 cases of severe Mycobacterium tuberculosis infection showing transient clinico-radiological improvements after incidental corticosteroid administration (without antituberculous treatment) leading to delayed diagnosis.

The first patient was a 35-year-old Indonesian woman who presented with fever, pleuritic chest pain, and dyspnea for 1 week (Table). She was admitted to the intensive care unit for respiratory failure and septic shock (Figure 1A). She was treated for community-acquired pneumonia and septic shock, with antibiotics and intravenous hydrocortisone (200 mg/day) for 6 days. She improved clinically (defervesce, extubated, blood pressure stabilized) and radiologically (Figure 1B). However, fever returned 3 days after steroid cessation and she required re-intubation 1 week later (Figure 1C). The diagnosis of miliary tuberculosis was subsequently confirmed by high-resolution computed tomography (CT) scan of the thorax and open lung biopsy (granulomata with acid-fast bacilli). She improved with antituberculous therapy plus a short course of corticosteroid.

Table

Clinical and Laboratory Findings for Cases 1 and 2 on Presentation

	Case 1 (F/35)	Case 2 (M/24)
Temperature (°C)	38.8	38.7
Blood pressure (mm Hg)	95/55	110/60
Pulse (beats per min)	109	105
Respiratory rate (breaths per min)	40	30
Arterial oxygen (kPa)	12.8 (with FiO2 1.0)	8.4 (on ambient air)
WBC (×109/L)	6.1	2.9
Neutrophil (×109/L)	5.6	2.3
Lymphocyte (×109/L)	0.5	0.5
Platelet (×109/L)	331	194
Hemoglobin (g/dL)	10.8	12.4
Prothrombin time (sec)	15.3	11.6
APTT (sec)	42.6	43
Sodium (mmol/L)	123	131
Urea (mmol/L)	3.8	6.0
Creatinine (umol/L)	50	92
Alanine aminotransferase (IU/L)	77	74
Plasma glucose (mmol/L)	5.7	4.2
HIV serology	NEG	NEG
Antinuclear antibody	<40	<40
Empirical antibiotics given	Cefotaxime 1 g 6 hourly for 6 days Clarithromycin 500 mg twice per day for 6 days	Co-trimoxazole (trimethoprim 720 mg/day) for 4 days Levofloxacin 500 mg daily for 7 days
Sputum AFB smear	NEG	NEG
BAL AFB smear	NEG	NEG
BAL bacterial culture	NEG	NEG
CT thorax and abdomen	1-mm miliary nodules, diffuse ground-glass opacities and consolidation, ileal-cecal inflammation	Bilateral ground-glass opacities and patchy consolidation
MTB culture	POS (sputum, urine, lung biopsy)	POS (lung biopsy)
MTB drug-susceptibility	Susceptible to all first-line agents	Susceptible to all first-line agents

WBC = white blood cell; APTT = activated partial thromboplastin time; HIV = human immunodeficiency virus; NEG = negative; AFB = acid-fast bacillus; BAL = broncho-alveolar lavage; CT = computed tomography; MTB = mycobacterium tuberculosis; POS = positive.

Figure 1

(A) Chest radiograph on admission showing bilateral confluent air-space infiltrates. (B) Chest radiograph after 6 days of corticosteroid showing resolution of infiltrates. (C) Chest radiograph 10 days after corticosteroid cessation, showing returned extensive infiltrates.

The second patient was a 24-year-old Chinese man who presented with fever, cough, and dyspnea (Table). He was initially treated for Pneumocystis jiroveci pneumonia with trimethoprim-sulphamethoxazole and prednisolone 80 mg daily. He improved promptly clinically and radiologically, but deteriorated again upon steroid withdrawal (Figure 2A-C). Later, miliary tuberculosis was confirmed by open lung biopsy.

Figure 2

(A) Chest radiograph on admission showing bilateral middle and lower zone infiltrates. A high-resolution CT thorax scan showed bilateral ground-glass opacities and patchy consolidation suggestive of Pneumocystis jiroveci pneumonia. (B) Chest radiograph after 4 days of corticosteroid showing resolution of infiltrates. The patient was also on levofloxacin day 5 for empirical bacterial coverage. (C) Chest radiograph 10 days after corticosteroid (and quinolone) cessation showing rapidly returning infiltrates.

Although transient resolution of fever is commonly observed, we further show that prompt (albeit partial and transient) radiological improvement is possible with corticosteroid administration without antituberculous agents in miliary tuberculosis. Although other possible explanations for the initial improvement (eg, treatment of co-existing bacterial pathogen, mycobactericidal effect of levofloxacin) cannot be ruled out. The observed associations are striking, and subsequent deterioration following corticosteroid withdrawal strongly supports its role. The partial improvements may mislead clinicians to attribute clinical responses to concomitant antibacterial therapy, thus delaying diagnosis of tuberculosis. Similar diagnostic pitfall has been reported with the empirical use of fluoroquinolone in pneumonia. Therefore, given its diverse clinical (including acute respiratory distress syndrome and multi-organ dysfunction) and radiological (eg, air-space consolidations, ground-glass appearances, lower lobe involvements)1, 3 features, it is prudent to investigate for tuberculosis in the context of unexplained sepsis1, 3 or severe pneumonia when corticosteroid is administered, and to avoid empirical fluoroquinolone treatment when tuberculosis cannot be safely excluded, particularly in areas with a moderate-to-high tuberculosis burden.

Corticosteroid has been used as “adjunctive” therapy in severe tuberculous infections (eg, meningitis, pericariditis, fulminant pneumonia) to reduce complications. Prompt clinico-radiological responses also are observed for Pneumocystis jiroveci pneumonia, severe acute respiratory syndrome, and varicella pneumonia, where immunopathogenesis is important. Skewed Th2 cytokine responses (eg, elevated interleukin-4, interleukin-10, and interleukin-13) are demonstrated in extensive/cavitatory pulmonary and miliary tuberculosis. Hyper-production of tumor necrosis factor-α and interleukin-1β, stimulated by lipoarabinomannan, also triggers acute lung injury. Corticosteroids can inhibit expression of these cytokines, suppressing symptoms. It is important for clinicians to be aware that corticosteroid may mask the diagnosis of tuberculosis. Delay in antituberculous treatment may lead to higher mortality.