Cryoglobulinemia is a rare disease characterized by presence of cryoglobulins, which are serum immunoglobulins that precipitate at low body temperature and re-dissolve with rewarming . There are three types of cryoglobulins according to Brouet et al., types I, II, and III . Type I is associated with lymphoproliferative diseases, while type II, and type III, called mixed cryoglobulinemia (MC), are associated with chronic infections mainly chronic hepatitis C virus (HCV) and less commonly chronic HBV infections, and sometimes with autoimmune diseases .
Type I cryoglobulins can precipitate at cold exposure resulting in hyper-viscosity and sludging, and patients present with Raynaud’s phenomenon, digital ischemia, livedo reticularis, and central nervous system involvement . Type II, and type III cryoglobulins (mixed cryoglobulins) can form immune complexes causing small to medium vessel vasculitis (Cryoglobulinemic vasculitis) in multiple tissues and organs [11, 12]. HCV-associated Cryoglobulinemic vasculitis (CV) is noted in 90–95% of cases, while hepatitis B virus-related Cryoglobulinemic vasculitis occurs in approximately 3% of cases only . Patients with mixed cryoglobulinemia can present with ‘Meltzer’s triad” of purpura, arthralgia, and weakness to more serious manifestations with skin, neurological, renal, and rarely pulmonary involvement .
Pulmonary manifestations have been reported, but appears to be very rare, and ranging from shortness of breath, interstitial lung fibrosis, hemoptysis, and/or diffuse alveolar hemorrhage to respiratory failure [13, 14]. While glomerulonephritis is noted in up to 90% of cases with MC, alveolar hemorrhage occurs in approximately 3.2% of patients with mixed cryoglobulinemia .
Ferri et al. studied the clinical manifestations of 231 patients with mixed cryoglobulinemia, but 21 patients (9.1%) were lost to follow- up at the end of the study. Mild exertional dyspnea was noted in 15 and 26% of patients at the beginning and end of follow-up, respectively . However, only 2% (four of 210) of patients had clinical/radiological evidence of interstitial lung involvement and only one patient was found to have hemoptysis. Of note, 92% of cases had hepatitis C virus (HCV) infection, whereas hepatitis B virus (HBV) considered the cause in only 1.8% of patients in that study . Bombardieri et al.  tested 23 MC patients with lung function studies. Of these, 20 had minimal to absent respiratory symptoms and, of those with severe respiratory symptoms, only one presented with hemoptysis. Noticeably, 18 of 23 patients had radiographic evidence of interstitial lung disease. Amital et al.  studied 125 patients hospitalized with cryglobulinemia over a 23-year period at their center. Of these, only four patients (3.2%) developed alveolar hemorrhage.
Trejo et al. had 7043 patients tested for circulating cryoglobulins, 443 (6.29%) patients had a cryocrit of 1% or more . Of the 443, 206 (47%) had clinical manifestations attributable to cryoglobulinemia during the progression of the disease. Pulmonary involvement was noted in 6 (1%) patients at onset of the disease, and in 9 (2%) During evolution of the disease . A cohort study performed by Ramos-Casals et al. analyzed 209 patients with cryoglobulinemic vasculitis. Twenty-nine (14%) patients had life-threatening cryoglobulinemic vasculitis . Of the 29, four patients had pulmonary hemorrhage. All had dyspnea, fever, hemoptysis, and pulmonary infiltrates on chest radiograph. The four patients died with no remarkable differences in the therapeutic regimens received by patients who died during the first episode and those who survived. Retamozo et al. study analyzed 279 HCV patients with cryoglobulinemia . Pulmonary hemorrhage noted in 18 (6.4%) patients. Among these 18 patients, pulmonary presentations ranging from respiratory failure in 11 (61.1%) patients, hemoptysis in 9 (50%), and dyspnea in 6 (33.3%) patients. Thirteen (72%) patients had concomitant glomerulonephritis .
As there are few reported cases of HBV-related cryoglobulinemic vasculitis, there are still no definitive treatment guidelines issued yet . According to Mazzaro et al. study published in 2016, a mono-therapy with antiviral agent nucleotide such as Lamivudine, Adefovir Dipivoxil, Entecavir, Telbivudine, or Tenofovir resulted in an excellent outcome in terms of viral clearance and clinical remission in HBV-related cryoglobulinemic vasculitis . While corticosteroid therapy was able to treat the clinical symptoms of vasculitis, it failed in suppression of HBV viremia and/or treating immuno-logical features as stated in Mazzaro et al. study . In Terrier et al. study, the use of corticosteroids and/or immunosuppressive agents with the lack of anti-viral agents were associated with refractory cryoglobulinemic vasculitis . However, rituximab in combination with antiviral agents led to complete and sustained clinical remission in patients with refractory or relapsing HBV-related cryoglobulinemic vasculitis per Terrier et al. [11, 20].
Therefore, HBV-induced MC with moderate to severe manifestations (eg, glomerulonephritis, cutaneous ulcers, progressive neuropathy, diffuse vasculitis including pulmonary and central nervous system vasculitis), similarly to HCV-associated MC, can be treated with antiviral therapy, glucocorticoids, and rituximab [12, 20,21,22]. And the role of immunosuppressive therapy such as rituximab is to sustain remission, decrease the cumulative glucocorticoid dose usage, and prevent any dramatic deterioration in a disease that studies showed only 22% survival in patients who presented with pulmonary hemorrhage [11, 18, 20].
Our unique case presented with a rare phenomenon of hemoptysis and alveolar hemorrhage as an initial presentation of cryoglobulinemic vasculitis without renal involvement and in the setting of unusual association with untreated chronic hepatitis B infection. Therefore, physicians must always carry high index of suspicion for cryoglobulinemic vasculitis when patients with HBV present with hemoptysis/alveolar hemorrhage after excluding other causes such as infectious or neoplastic diseases. Bilateral lung infiltrates in such patients should warrant further investigation with bronchoscopy, as pulmonary hemorrhage on BAL is strongly suggestive of vasculitis . As our case revealed, early bronchoscopy and diagnosis with a prompt treatment with corticosteroids, immunosuppressive agents (Rituximab), and antiviral therapy (Entecavir) resulting in a favorable outcome and improved patient survival. Our decision to start rituximab was on basis of the effectiveness of this option in patients with HCV-associated MC with moderate to severe signs of systemic vasculitis which our case can be considered under this category.
On our literature review, pulmonary vasculitis with primary hemoptysis caused by mixed cryoglobulinemia reported few times either in case or cohort studies as far as we noticed. Most of these cases had renal involvement with glomerulonephritis and were associated with HCV infection . Most of these cases were treated with pulse methylprednisolone with other immunosuppressive therapy such as cyclophosphamide, rituximab, azathioprine, plasmapheresis, and commencing antiviral therapy . However, pulmonary vasculitis and hemorrhage still have very poor prognosis despite appropriate management .
Due to the rarity and poor prognosis of pulmonary hemorrhage in mixed cryoglobulinemia, as well as the unusual association with hepatitis B infection, physicians must have a high index of suspicion for the disease to commence early treatment and reduce patient morbidity.