Polyarteritis nodosa presenting as a febrile rash and severe fatal myocarditis

Ziglam HM, France AJ, Evans A and Nathwani D.

Department of Infection & Immunodeficiency, Ninewells University Hospital & Medical School Dundee, DD1 9SY

SMJ 2006 51(1): 57

 

Abstract:

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small and medium sized muscular arteries. The spectrum of the clinical presentation can range from an apparently limited disease to fulminant poly-visceral failure. We report a fatal case of isolated cardiac PAN presenting as an acute febrile rash and hypotension.

Keywords: Polyarteritis nodosa, vasculitis, myocarditis

 

Introduction: 

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small and medium sized muscular arteries.  The frequency of cardiac manifestations range from 0 to 86%, and include pericarditis, myocardial infarction, electrocardiographic (ECG) abnormalities and congestive heart failure [1, 2] . Acute myocarditis as a solitary cardiac feature of PAN is very rare and to our knowledge has not been previously reported in the context of the clinical presentation below.

 

We report this fatal complication in a 63-year-old woman presenting with fever, rash and hypotension.  

Case history:

Our patient presented with 5-day history of sore throat, fever, severe headache, and a widespread itchy rash 48 hours preceding hospital admission. She had been previously well except for a road traffic accident in 1988 when she sustained multiple injuries including fracture of cervical spine requiring fixation with a metal plate. She was a non-smoker and drank alcohol occasionally. There was no history of recent travel;   she had no pets or evidence of animal contact prior to admission.

On examination, the patient appeared unwell with a temperature of 38.1°C, pulse 96/min, and a respiratory rate of 20/min. Initial blood pressure was 70/40 mmHg. There was generalized erythematous macular rash with an urticarial component over her body. A few "shotty" and tender cervical lymph nodes were palpated.  Physical examination was otherwise normal.   Abnormal laboratory tests on admission were CRP 183 mg/l, hemoglobin 86 g/l leukocyte 18x109l, platelets 138x109l, alkaline phosphate 478 u/l, and ALT 146 u/l. Urine dipstick and microscopy studies showed minimal (+1) proteinuria. Prothrombin time was 13.54 sec (INR 1.3), partial thromboplastin time 32.1 sec, and fibrinogen 2.0 g/l. Immunoglobulin (Ig) electrophoresis was normal apart from the IgM which was 5.96 g/L (normal 0.50-2.50 g/L).  Cold-agglutinins and autoantibodies (ANA, ANCA, and AMA) were negative but the anti SMA antibody was (++) positive. Serological tests for HAV, HBV, HCV, HIV, Leptospira interrogans, Rickettsiae, Legionella pneumophila, Chlamydia psittaci, echoviruses, coxsackie viruses, and adenoviruses were negative. CMV IgM preformed on admission was weakly positive. Repeat serology was not performed.  Electrocardiogram was normal apart form sinus tachycardia.

 

The patient was treated with high flow oxygen (100%), intravenous (iv) co-amoxiclav, iv clindamycin and iv fluid support. On the following day the antibiotic regimen had been broaded by changing to piperacillin/tazobactam and iv immunoglobulin (0.4gm/ Kg per day for three days) was commenced.

On the fourth day post admission, the patient became more unwell with shortness of breath due to new onset of atrial fibrillation (AF; heart rate≥ 160). Despite commencement of digoxin, her heart rate proved difficult to control optimally. Repeat ECG showed no other abnormalities except AF. An echocardiogram was not preformed. Despite this her overall symptoms of fever, rash and blood pressure continued to slowly improve and stabilise.  Her dyspnoea appeared to respond to intravenous diuretic (frusemide) therapy. On the day seventh after admission died of a ventricular fibrillation induced cardiac arrest. Postmortem examination revealed evidence of widespread and severe myocarditis with a diffuse mixed inflammatory cell infiltrate which extend to involve the pericardium. There was also obvious vasculitis involving sizeable muscular vessels within the myocardium and pericardium. In addition, some of the vessels were associated with aneurysm formation. The features indicate a florid myocarditis with vasculitis (figures 1-3). The other organs including liver, kidneys, lungs and gastrointestinal system were normal with no convincing evidence of vasculitis. The diagnosis was PAN with myocarditis only but no histopathological evidence of CMV infection or a "toxic" myocarditis. 

Discussion:

In this report we describe an unusual case of PAN only affecting the heart presenting with a fulminant course characterized by fever, rash, hypotension and abnormal liver function tests followed by drug resistant atrial fibrillation, heart failure and fatal cardiac arrest. 

The term "polyarteritis nodosa" was first used by Kussmaul and Maier in 1866 [3] . PAN is a systemic, necrotizing vasculitis primarily involving medium and small-sized visceral arteries, such as coronary, hepatic, renal, and mesenteric arteries, and their major branches. The lesions are segmental and tend to involve bifurcations.  They may spread circumferentially to involve adjacent veins [4] . However, localized polyarteritis and vasculitis has been reported to occur in the muscles, gallbladder, pancreas, bowel and appendix [5-7] . The initial clinical syndrome was not typical of PAN. There was no evidence of pre-existing hypertension; no other organs appeared to be involved especially no haematuria. Our admission working diagnosis was either of bacterial toxic shock syndrome [8] or a systemic viral illness such as CMV infection. This was the rationale behind the initial antibiotic regimen and use of immunoglobulin [9] .  

This case illustrates the potential difficulty in making the ante-mortem diagnosis of PAN, particularly when presenting in an atypical manner. The condition is rare with an estimated incidence and prevalence of 4.6 per 100 000 in England [10] . In addition to being uncommon, PAN typically presents with non-specific constitutional symptoms (for example fever, malaise, and weight loss). The spectrum of the clinical presentation can range from an apparently limited disease to fulminant poly-visceral failure [10] . There is no single pathognomic feature of the disease or common clinical presentation to suggest PAN as a diagnosis.

 

Interestingly PAN has been described in association with a variety of infectious agents. Hepatitis B virus,  group A streptococcal infections,  hepatitis C virus, human T cell leukaemia virus-1, cytomegalovirus, HIV, and human parvovirus B19 [10, 11] . However, in this case an extensive search for infectious agents proved negative apart from CMV which was weakly positive. Severe myocarditis linked to CMV infection appears to be a rare event although fatalities attributed to progressive heart failure have been reported [12, 13] . Acute CMV infection has been linked to ANCA-associated vasculitis in non-immunocompromised patients either as a causative agent or an opportunistic infection.. The postmortem histology, however, did not show any evidence of active CMV infection.

 

The diagnosis of classical  PAN requires fulfillment of a range of clinical, laboratory, histological and radiological criteria as outlined by the American College of Rheumatology (table). Three out of 10 of these represent  a sensitivity of 82.2% and a specificity of 86.6% [15] .

 

 Table: American College of Rheumatology Guidelines for the Diagnosis of Polyarteritis Nodosa.

  • Unexplained weight loss >4 kg

  • Livedo reticularis

  • Testicular pain or tenderness

  • Myalgia, muscle weakness, or leg tenderness

  • Mononeuropathy or polyneuropathy

  • Diastolic blood pressure >90 mm Hg

  • Elevated level of blood urea nitrogen or creatinine

  • Presence of hepatitis B surface antigen or antibody in serum

  • Arteriographic abnormalities not resulting from other disease

  • Biopsy of small or medium-sized artery containing granulocytes

 

Whilst the underlying pathogenesis is poorly understood, vasculitis reflects an inflammatory process resulting from a disordered immunological reaction within the wall of the affected vessels; thereby retrospectively the potential role of steroids and immunosuppressive therapy remain the cornerstones of treatment. However, high dose of steroid may be potentially harmful in the presence of severe sepsis. In the absence of easy diagnostic tests the value of using empiric steroids in this setting remains not clear.

 

In conclusion this case illustrates the difficulty in making an ante-mortem diagnosis of PAN affecting a single relatively inaccessible (for histological biopsy) organ. Radionuclide imaging or echocardiography would also not confirm the diagnosis. An antemortem biopsy would not be without considerable morbidity and mortality. We would urge clinicians to consider this rare diagnosis in patients presenting with a febrile rash where there is persistent hypotension, resistant cardiac dysarrhythmia and cardiac failure despite the absence of renal or other organ involvement.

 

References:

1.         Fink, C.W., Polyarteritis and other diseases with necrotizing vasculitis in childhood. Arthritis Rheum, 1977. 20(2 Suppl): p. 378-84.

2.         Fink, C.W., Vasculitis. Pediatr Clin North Am, 1986. 33(5): p. 1203-19.

3.            Kussmaul, A.M., K, Uber eine bisher neiht beschriebene eigenthumliche Arterienerkrankung die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskellahmung einhegt. Deutch. Arch. Klin. Med., 1866. 1: p. 484.

4.            Jennette, J.C.R., S., Vasculitis. 1996 ed. Vol. Part 4, Chap. 47. 1996, Missouri: Mosby-Year Book. 1429-1431.

5.            Kamimura, T., et al., Muscular polyarteritis nodosa as a cause of fever of undetermined origin: a case report and review of the literature. Rheumatol Int, 2005. 25(5): p. 394-7.

6.            Kubosawa, H., et al., Localized necrotizing angiitis of the ileum. Pathol Int, 2003. 53(3): p. 186-90.

7.         Kumar, B., et al., Isolated necrotizing vasculitis of gallbladder: a report of two cases and review of literature. Indian J Pathol Microbiol, 2003. 46(3): p. 429-31.

8.         Davis, J.P., et al., Toxic-shock syndrome: epidemiologic features, recurrence, risk factors, and prevention. N Engl J Med, 1980. 303(25): p. 1429-35.

9.            Darenberg, J., et al., Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis, 2003. 37(3): p. 333-40.

10.            Guillevin, L., et al., Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum, 1999. 42(3): p. 421-30.

11.       Mader, R. and E.C. Keystone, Infections that cause vasculitis. Curr Opin Rheumatol, 1992. 4(1): p. 35-8.

12.       Tiula, E. and P. Leinikki, Fatal cytomegalovirus infection in a previously healthy boy with myocarditis and consumption coagulopathy as presenting signs. Scand J Infect Dis, 1972. 4(1): p. 57-60.

13.       Waris, E., et al., Fatal cytomegalovirus disease in a previously healthy adult. Scand J Infect Dis, 1972. 4(1): p. 61-7.

14.            Hoffman, G.S. and U. Specks, Antineutrophil cytoplasmic antibodies. Arthritis Rheum, 1998. 41(9): p. 1521-37.

15.            Lightfoot, R.W., Jr., et al., The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum, 1990. 33(8): p. 1088-93.

 

Back to February Contents