Granulomatosis with polyangitis with mononeuritis multiplex-immunosuppressives playing a double-edged sword.

A 52-year-old female was diagnosed with rheumatoid arthritis and was on methotrexate and prednisolone. She developed fever, cough, hemoptysis, and cavitary lesion on chest skiagram. She was put on antitubercular therapy without any improvement, meanwhile she developed painful right foot drop. Clinicoradiology and C-ANCA study confirmed the diagnosis of granulomatosis with polyangitis (GPA). She was started on cyclophosphamide, corticosteroid, and co-trimoxazole. While her treatment was being continued she showed significant improvement of pulmonary manifestations. About 1 year later, there was reappearance of fever, cough, and radiological opacity with oropharyngeal candidiasis. She became very ill with disseminated intravascular coagulation (DIC)-like features. Immunological markers were negative but bronchoalveolar lavage fluid study showed growth of Aspergillus spp. The patient was promptly put on intravenous voriconazole but unfortunately she succumbed to her illness.

INTRODUCTION

Wegener's granulomatosis (WG), which has been recently renamed as Granulomatosis with polyangitis (GPA)[123] is a systemic vasculitis involving small and medium vessels. Although classical GPA presents with a triad of upper respiratory tract, pulmonary and kidney involvement, uncommonly patients with atypical presentation puts the clinicians in diagnostic as well as therapeutic dilemma. Here we report a case of GPA with mononeuritis multiplex with more than 1-year follow up showing the therapeutic challenges that clinicians may come across during the course of treatment.

CASE REPORT

A 52-year-female was on methotrexate and prednisolone since September 2011 with a diagnosis of rheumatoid arthritis. She developed fever and cough with scanty hemoptysis in March 2012; she was thought as a case of smear negative pulmonary tuberculosis in a patient on immunosuppressives and was put on antitubercular drugs. She took the antitubercular drugs for 2 months but her clinical condition worsened and she presented to our department. On further enquiry, she gave a history of symmetrical arthralgia of small and medium joints of hands for last 2 years without a definite history of joint swelling or morning stiffness and history of recurrent attacks of ear infections. She denied the history of oliguria, hematuria, skin lesions, oral or genital ulcer, or ocular symptoms. On examination, there was pallor, tachypnoea, tachycardia, but cyanosis and clubbing were absent, her blood pressure was 160/90 mm-Hg. Examination of the respiratory system was unremarkable apart from the presence of crepitations in both lower zones, examination of other systems were within normal limits. On the third day of admission, she developed tingling sensation in the right leg in the morning with development of painful sudden foot drop in the same day evening [Figure 1]. Neurological examination revealed absent ankle jerk, very weak (1/5) power of both dorsiflexors (tibialis anterior, extensor hallucis longus and extensor digitorum longus and extensor digitorum brevis), and plantar flexors (gastrocnemius, soleus, flexor hallucis longus and flexor digitorum longus); she was also unable to evert or invert the right foot. Sensory testing revealed mixed sensory loss over anterolateral aspect of lower leg and right foot not conforming to any specific nerve area. Neurological examination was normal in all other limbs. Her ear examination revealed the presence of bilateral chronic suppurative otitis media.

Figure 1

Photograph showing right foot drop

Complete hemogram revealed - hemoglobin - 8 gram/dl, total leucocyte count (TLC) - 14600/cmm with a neutrophilic predominance, blood sugar fasting was 156 mg/dl and postprandial sugar was 212 mg/dl. Serum urea and creatinine were within the normal limits and urine for routine and microscopic examination did not show any RBC or cast. Sputum for AFB was negative on two occasions. Chest X-ray PA view revealed consolidation and nodular shadows in both lower zones [Figure 2]. Contrast-enhanced computed tomography (CECT) scan of thorax also corroborated with the chest x-ray findings [Figure 3]. Immunological markers showed rheumatoid factor positive in high titer (100.8 IU), but anti-CCP antibody was negative; antinuclear factor (ANF) and anti-ds-DNA antibody were negative; cytoplasmic antineutrophilic cytoplasmic antibody (C-ANCA) was positive in high titer (96.7 IU by the ELISA method) but P-ANCA was negative. Nerve conduction velocity (NCV) revealed nonrecordable compound muscle action potential (CMAP) in right peroneal and grossly reduced CMAP in right tibial nerve with absent sensory nerve action potential (SNAP) in right sural nerve. Right tibial and peroneal “F” responses were absent and so was right “H” reflex. NCV study of all four limbs were consistent with sensory-motor axonal involvement in right tibial and peroneal nerves and was consistent with mononeuritis multiplex of the right leg. Echocardiography and ultrasound of abdomen were normal. Patient was diagnosed as GPA with pulmonary involvement and mononeuritis multiplex.

Figure 2

Chest x-ray (March 2012) showing consolidation with multiple nodules in both lower zones

Figure 3

CT scan of thorax (March 2012) showing multiple nodules in both lower lobes

She was immediately started on intravenous pulse cyclophosphamide (750 mg) on day 1 with intravenous pulse methylprednisolone 1 g for three consecutive days (day 1-3). Patient showed significant clinical improvement regarding pulmonary symptoms. She was then maintained on prednisolone 40 mg/day, oral cyclophosphamide 100 mg/day, and cotrimoxazole tablet. Follow-up chest X-ray showed significant improvement at the end of 3 months and near complete resolution of radiological lesions after 6 months [Figure 4] with negative C-ANCA; but her foot drop persisted. Steroid was tapered gradually and was stopped at the end of 9 months while cyclophosphamide and co-trimoxazole were being continued. She was euglycaemic with oral hypoglycemic agents. In June 2013, she again developed fever with cough, anorexia, and dysphagia; on examination pallor was present and there were multiple ecchymoses over both hands. Examination of oropharynx revealed oropharyngeal candidiasis. Chest x-ray showed reappearance of consolidation with a cavity in right lower zone; sputum for AFB was negative on two occasions, blood counts showed anemia, TLC- 3100/cmm with neutropenia, thrombocytopenia (45000/cmm); serum urea, creatinine, blood sugar, electrolytes were within normal limit; serum bilirubin was 2.1 mg/dl with increased liver enzymes (SGPT- 274, SGOT- 233), though hepatitis profile was negative. C- ANCA was negative as well. Septicaemia with disseminated intravascular coagulation (DIC) was suspected; blood culture (aerobic and anaerobic) did not yield any growth and her coagulation profile showed prolongation of prothrombin time and activated partial thromboplastin time, with increased level of fibrin degradation products-compatible with the diagnosis of DIC. Cyclophosphamide was stopped and patient was put on broad spectrum antibiotics with intravenous meropenem and moxifloxacin with intravenous fluconazole, but she did not show any clinicoradiological response in next 48 h; current CECT Thorax showed cavity in the lower-right lobe with surrounding satellite nodules [Figure 5]; fiberoptic bronchoscopy was performed and bronchoalveolar lavage fluid culture showed growth of Aspergillus spp. Fluconazole was replaced with intravenous voriconazole (6 mg/kg twice a day). Unfortunately, the patient succumbed from the invasive fungal infection on fifth day after starting voriconazole.

Figure 4

Follow-up chest x-ray after 6 months showing near complete resolution of radiological opacities

Figure 5

CT scan of thorax (June 2013) showing single large cavitary lesion in lower-right lobe with satellite nodules

DISCUSSION

GPA is a systemic pauci-immune vasculitis associated with ANCA. The clinical entity was first described by Friedrich Wegener in 1936 and since then it is widely known as WG in the medical literature; the disease nosology was changed of late to GPA.[13] Pulmonary involvement is common, being present in 90% cases; manifestations are protean but multiple nodules with or without cavitation, fleeting pneumonia, unilateral or bilateral pleural effusion, and diffuse alveolar hemorrhage are common.[456] Recurrent otitis media and epistaxis are common upper airway symptoms. Although neurological involvement is more prevalent in churg-strauss syndrome, it is seen in GPA as well. Rarely neurological manifestations may be the initial presentation.[7] Peripheral neuropathy in the form of mononeuritis multiplex is the commonest neurological manifestation.[8] Demonstration of necrotizing vasculitis and granuloma on biopsy is confirmatory for diagnosis of GPA, but a high index of clinical suspicion combined with a positive C-ANCA in high titer by the ELISA method is also sufficient for the diagnosis of GPA in the absence of biopsy.[9] Prognosis of GPA has dramatically improved with the introduction of combined cyclophosphamide and prednisolone, with high remission and 5-year survival rate.[10] Worsening of a patient during therapy or remission phase with reappearance of pulmonary symptoms and new opacity on chest x-ray are often due to flaring up or relapse of the primary pathology, but infections with organisms such as Mycobacterium tuberculosis, Pneumocystis jiroveci, or opportunistic fungal infections have to be seriously considered, too, specially because of ongoing immunosuppressive therapy for such a long duration.[1112] Older age, renal involvement, and infection are found to be the adverse prognostic factors and infection is reported to be the one of the commonest cause of mortality.[1113] Abtahi et al.[14] reported a case of sinusal mucormycosis in a case of WG, 2.5 years after the initial diagnosis. Berenguer et al.[15] and Noguiera[16] et al. have also reported pulmonary mucormycosis mimicking disease relapse in patients with WG on immunosuppressive therapy. Invasive pulmonary aspergillosis in patients with GPA have also been reported in the literature.[1718] Incidence of disseminated fungal infection leading to DIC is very rare but is associated with a fatal outcome with high mortality.[19] In our case also the patient showed very good response to cyclophosphamide plus prednisolone therapy, but unfortunately developed oropharyngeal candidiasis and pulmonary aspergillosis with DIC and ultimately succumbed from the infection.

To conclude, in the management of systemic vasculitis, immunosuppressive agents can act as a double-edged sword; on one hand these are life saving and have improved the prognosis of vasculitides to a great extent and on the other hand they make patients more vulnerable to infections with opportunistic pathogens like fungi, which may disseminate and can be fatal. Clinicians should keep a very close vigil on the vasculitis patients on immunosuppresants for earliest detection and appropriate aggressive therapy to combat these opportunistic fungal infections.