Thrombotic Microangiopathy Secondary to Disseminated Varicella Zoster Virus Infection in an Adult Patient

Background

TMA is a syndrome characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and renal failure. It encompasses the spectrum of classical thrombotic thrombocytopenic purpura (TTP) described first by Moschowitz [1], and HUS described 3 decades later by Gasser et al [2]. TMA has been associated with various triggering factors, including infections, illicit drug use, neoplasms, connective tissue disorders, and pregnancy [3–5]. Direct endothelial injury is the proposed pathogenesis mechanism for the development of TMA. It is characterized by thickening of the arterioles, endothelial swelling, intraluminal platelet thrombi, and fragmentation of red blood cells (RBC) as blood flows across the partially occluded microcirculation. A few reports, such as Basnayake (2020) [6], showed an association between TMA and VZV infection, and the majority were in the pediatric age group. In the present report, we discuss a case of TMA induced by a disseminated VZV infection in an adult with a diagnostic challenge but a successful outcome.

Case Report

OUTCOME AND FOLLOW-UP:

Upon discharge, the patient had improved, and his renal functions, platelet count, and LDH levels had normalized (Figure 2). After a 21-day stay in the hospital, the patient was released on a tapering dose of steroids with a follow-up arranged in 2 weeks. Unfortunately, the patient traveled to his home country and was lost further follow-up.

Discussion

Viruses are important in the development of TMA; many are only linked to HUS or aHUS, but some can cause TTP. The pathophysiology of TMA induced by viruses is unknown. On the other hand, direct endothelial cell damage appears to be an important pathology trigger [7–9]. Furthermore, host genetic or environmental susceptibility factors may provide a favorable environment for viruses to initiate the chain of events that result in TMA’s clinical manifestations. Although certain reports of viral-related TMA are based on anecdotal evidence, such correlations cannot be ruled out [7–10].

Varicella is predominantly a childhood disease characterized by vesicular exanthema frequently accompanied by fever and malaise. Human VZV disseminates to the viscera during viremia and multiplies in reticuloendothelial tissues. Varicella usually manifests as mild to moderate illness, but serious complications (eg, meningoencephalitis, meningitis, vasculitis affecting small or large vessels, pneumonia, and hemorrhages) can arise. There is only 1 previous report of this type of HUS following varicella infection [11].

Primary VZV infection in adults has a more severe presentation, including interstitial pneumonia, in comparison to younger age groups. In addition, the infection produces severe, disseminated diseases in immunocompromised individuals. More than 90% of people are infected before adolescence, with 13–16 cases per 1000 people per year. In tropical climates, however, VZV infection occurs later in life. Varicella has a peak incidence in the late winter and spring, and epidemics tend to occur every 2–5 years [12,13].

Fever and a self-limiting rash on the skin, and occasionally the mucosa, are symptoms of varicella. Headaches, malaise, and a loss of appetite are also common. Macules are the first signs of the rash and rapidly progress to papules, followed by a vesicular stage and crusting of lesions. VZV is highly infectious, and transmission occurs by direct contact with skin lesions or respiratory aerosols from infected individuals. Central nervous system complications include self-limiting cerebellar ataxia in 1 in 4000 cases, meningitis, meningoencephalitis, and vasculopathy. Stroke may occur months after varicella, secondary to VZV vasculopathy, and are not always easy to diagnose [12,13].

Our patient presented with a varicella infection associated with macular rash and fever followed by renal failure and seizure.

He was investigated for TTP, but ADAMTS13 testing was reported to be normal. Given the presence of MAHA, thrombocytopenia, and renal failure, we believe that this was a case of TMA, with a high probability of an atypical form of HUS. The patient showed improvement after receiving multiple sessions of plasma exchange and steroids.

New algorithms for managing MAHA, thrombocytopenia, and renal failure have developed because the frequency of different kinds of HUS varies by age [12,13]. In our case, the negative E. coli 0157: H7 shiga-like exotoxin and the shiga toxin assays excluded atypical HUS, and TTP was excluded by the lack of severe ADAMTS13 deficiency, resulting in lack of a definitive diagnosis. The present consensus is that plasma exchange for 5 days should be used as a first-line treatment [12]. If an inadequate response to medication fails to normalize LDH, platelet count, or lower creatinine level by more than 25%, eculizumab therapy should be started, but our patient’s LDH and creatinine levels improved despite the lag in platelet count improvement.

Conclusions

TMA is a life-threatening hematological emergency with a high mortality rate if not identified and treated early. Identifying the etiology may help guide the management.

VZV infection tends to be more severe in the adult age group compared to the pediatric population. Many viral infections are known to be associated with TMA [4,7].

To the best of our knowledge, this is the first reported case of TMA as a complication of VZV infection in an adult. A high index of suspicion for TMA in adult patients with VZV who present with thrombocytopenia, even when there is no definitive diagnosis, can result in early management with favorable outcome.