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CASE PRESENTATION

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. PATIENT'S COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

History of the present illness

A 36-year-old female nurse in whom a previous diagnosis of central nervous system (CNS) vasculitis had been made was transferred to our institution for hypoxemic respiratory failure. Two weeks prior to admission, she bumped her left leg against a chair and developed an abscess that was treated with cefazolin. A culture showed coagulase-negative staphylococcus and light growth of gram-positive bacilli. A week later she developed progressive dyspnea. A chest radiograph at a local institution demonstrated bilateral interstitial infiltrates and bronchoalveolar lavage grew “usual flora.” A transbronchial biopsy showed non-necrotizing granulomas. An extended culture from the previous leg wound demonstrated growth of Actinomyces israelii, susceptible to clindamycin and penicillin. She was asked to come in to the hospital for treatment, but experienced respiratory arrest at the admission desk and was admitted to the intensive care unit for bilevel positive airway pressure (BIPAP) therapy. Clindamycin (due to a penicillin allergy) and empirical amphotericin were started for presumed actinomycosis. Intravenous (IV) methylprednisolone (1,000 mg × 2 doses) was also given for the presumptive vasculitic process. She was then transferred to our institution by air ambulance on high-dose oxygen supplementation.

Medical history

The patient was diagnosed with CNS vasculitis 7 months earlier. She initially presented with diplopia and was evaluated by the ophthalmology department, which thought this represented a small-vessel occlusion in the right eye. She subsequently developed paresthesia in the right hand and headaches. Her initial evaluation included an elevated C-reactive protein (CRP) level of 6.8 mg/dl (normal range 0–1.3) and erythrocyte sedimentation rate (ESR) of 30 mm/hour (normal range 0–20), and positive antinuclear antibody (ANA) of 200 units/μl (positive at >120) with negative double-stranded DNA. Magnetic resonance imaging (MRI) of the brain demonstrated multiple small infarcts of varying age, ranging from acute to chronic, in the bilateral frontal and parietal lobes involving the cortex and subcortical white matter, and in the splenium of the corpus callosum. There was concern regarding posterior reversible encephalopathy syndrome. She was initially started on clopidogrel and prednisone. Followup testing demonstrated normal magnetic resonance angiography (MRA) of the head and neck. Her presentation was believed to be consistent with CNS vasculitis. She received prednisone and monthly IV cyclophosphamide (5 doses). However, she developed hematuria as a result of the cyclophosphamide and was switched to daily azathioprine therapy.

Social and family history

Her history included previous tobacco use, with a total of 5 pack-years. She denied any recent travel. She had no family history of autoimmune or pulmonary conditions.

Review of systems

She denied arthralgias, hemoptysis, photosensitivity, ulcers, Raynaud's phenomenon, fever, and rash, with the exception of the raised erythematous lesion on her left lower extremity.

Physical examination

Vital signs included a temperature of 36.8°C, pulse of 97 beats per minute, blood pressure of 157/86 mm Hg, respiratory rate of 26 breaths per minute, and oxygen saturation of 94% on BIPAP with a fraction of inspired oxygen of 1.0. Her lungs were clear to auscultation. A cardiac examination revealed no murmurs. On the left shin, there was an erythematous nodule with sutures from a previous biopsy site. There was no arthritis or rheumatologic skin rashes.

Laboratory tests and imaging

Laboratory studies included hemoglobin of 12.1 gm/dl (normal range 12–15.5), leukocytes of 17.9 × 109/liter (normal range 3.5–10.5), and platelets of 457 × 109/liter (normal range 150–450). The ESR was elevated to 39 mm/hour (normal range 0–29) and the CRP level was elevated to 21.2 mg/liter (normal value <8). Creatinine was normal at 0.8 mg/dl (normal range 0.6–1.1), with urinalysis showing no casts. ANA was negative by enzyme-linked immunosorbent assay at 0.4 units (normal value <1), but was positive on indirect immunofluorescence at a 1:160 titer with a speckled pattern. Antimyeloperoxidase and anti–proteinase 3 antibodies were negative. A computed tomography (CT) scan of the chest showed diffuse tree-in-bud–like micronodular infiltrates with subtle centrilobular ground-glass opacities and several enlarged mediastinal lymph nodes (Figure 1). A transthoracic echocardiogram demonstrated elevated right ventricular systolic pressure (88 mm Hg) with a severely enlarged right ventricle and decreased function, which was confirmed on right-sided heart catheterization. There was no evidence of a shunt at the atrial level by color flow imaging. A V/Q scan did not demonstrate any evidence of pulmonary embolism. MRI of the brain showed multiple small new acute and subacute enhancing infarcts in multiple vascular distributions in both hemispheres, and cerebellum and embolic etiology was suggested. Head and neck MRA was normal and cerebral angiogram showed no evidence of vasospasm or vasculopathy.

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Figure 1. Computed tomography scan of the chest showing diffuse tree-in-bud–like micronodular infiltrates with subtle centrilobular ground-glass opacities and several enlarged mediastinal lymph nodes.

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CASE SUMMARY

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. PATIENT'S COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

This is a case of a 36-year-old woman with acute hypoxemic respiratory failure with associated diffuse pulmonary infiltrates, severe pulmonary hypertension, and diffuse CNS infarcts.

DIFFERENTIAL DIAGNOSIS

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. PATIENT'S COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

It was difficult to initially identify a unifying diagnosis for the patient's multiple findings. The chest CT scan showed a “tree-in-bud” pattern of infiltrates. This term is used to describe small centrilobular nodules connected to multiple branching linear structures that originate from a single stalk, similar to a budding tree in spring. Numerous conditions can lead to this radiographic appearance, including infectious etiologies (1). Due to her immunocompromised status and the growth of A israelii from the outside wound culture, concern arose regarding infection. The differential diagnosis for infectious organisms in this patient was vast and included bacterial, viral, fungal, and mycobacterial pathogens (2). This could potentially be linked to the findings of CNS infarcts via septic emboli. However, the patient had not responded to broad-spectrum antibiotics and the outside bronchoalveolar lavage was unrevealing.

Another potential explanation was interstitial lung disease related to a rheumatologic condition. This could have caused secondary pulmonary hypertension. However, the patient did not have any historical signs or symptoms to suggest a rheumatologic condition such as rheumatoid arthritis or Sjögren's syndrome. Furthermore, serologies were negative, with the exception of ANA by immunofluorescence. Also, it was unclear how to explain the infarcts, since the angiogram did not suggest a vasculitic process. Diffuse alveolar hemorrhage could be considered but was not supported by the outside bronchoalveolar lavage; moreover, it would not provide an explanation for the CNS findings.

Malignancy is another consideration, since tumor embolism can result in these chest CT findings. However, the CNS findings were not consistent with metastatic disease.

Sarcoidosis could be a unifying diagnosis for pulmonary infiltrates and CNS findings. Sarcoidosis can present initially with infarcts based on case reports (3). The outside biopsy had noted rare non-necrotizing granuloma. The poor response to steroids, however, somewhat provided evidence against this.

Drugs such as cyclophosphamide can result in pulmonary toxicity with findings of pulmonary infiltrates. The pattern of early-onset pneumonitis should have responded to cessation of the cyclophosphamide as well as corticosteroids. A late onset can occur despite cessation of cyclophosphamide. Pleural thickening has been reported in some case series, which this patient did not demonstrate. This would be a diagnosis of exclusion and would require elimination of other diagnoses (4).

A thromboembolic disorder was also considered to explain both the pulmonary hypertension and CNS infarcts. However, the V/Q scan failed to show any evidence of thromboembolic disease. Furthermore, the thrombophilia evaluation had been unrevealing.

PATIENT'S COURSE

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. PATIENT'S COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

Infectious studies, including blood, cerebrospinal, and skin lesion cultures, were negative both for bacteria and mycobacteria; an interferon-γ–release assay was also negative. Human immunodeficiency virus testing was negative. Cerebrospinal fluid protein was 31 mg/dl (normal range 0–35), glucose was 58 mg/dl, and there was one nucleated cell with no abnormal cells or oligoclonal bands. A transthoracic echocardiogram continued to show elevated right ventricular systolic pressure at 66 mm Hg. A transesophageal echocardiogram was performed to rule out an embolic source. Although no vegetations were identified, an incidental patent foramen ovale was noted.

Due to an unclear explanation of her symptoms, the outside pathology sample was reviewed. This demonstrated non-necrotizing granulomatous inflammation with increased eosinophils and polarizable foreign material identified therein (Figure 2). Both the inflammatory infiltrate and the foreign material were located primarily in a periarterial distribution, raising the possibility of a vascular origin (i.e., IV drug usage). The age of these lesions was difficult to determine due to the limited sample. The combination of the polarizable material and appearance of the granulomas was most consistent with talcosis rather than tuberculosis or sarcoidosis. The patient had repeatedly denied a history of drug abuse; however, when confronted with the biopsy results, admitted to injecting crushed oxymorphone tablets. Two years prior to presentation she had developed worsening migraine headaches and was prescribed oral oxycodone and oxymorphone. Due to several personal stressors, she escalated use of these drugs and eventually moved to other routes of administration, including crushing, snorting, and IV injection. At the insistence of her family, she checked into an inpatient chemical dependency facility and was completely abstinent after completion of the treatment. She attended Narcotic Anonymous weekly. Her attendance waned in the fall of 2010 due to medical problems, resulting in a relapse.

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Figure 2. A, Lungs with non-necrotizing granulomatous inflammation and increased eosinophils in a perivascular distribution. B, Presence of birefringent foreign material was noted in granulomas (arrowhead). C, Higher magnification (× 40) view of talc crystals.

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At our institution, a chemical dependency consult was placed and the patient agreed to go back to Narcotic Anonymous. For pulmonary hypertension she was started on inhaled treprostinil, tadalafil, and warfarin. Prednisone was tapered off. Three months later, she returned for followup and is asymptomatic in terms of pulmonary hypertension, although the infiltrates persist.

DISCUSSION

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. PATIENT'S COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

This case highlights the need for a high index of suspicion for noninfectious causes of pulmonary infiltrates. The initial evaluation in an immunocompromised host is directed toward excluding infection (typical or atypical). The pattern on CT scan can sometimes provide a clue toward diagnosis. Although very rare, the patient's CT appearance has also been noted in IV drug abusers who inject street drugs contaminated with fillers such as talc (magnesium silicate), cellulose, or cornstarch (5, 6). Our patient was injecting crushed oxymorphone tablets intravenously. These pills contain talc and hydroxymethylcellulose as binding and bulking agents (7). Crushed tablets can either be snorted or injected intravenously. Inhalation leads to deposition around the alveolar ducts and terminal and respiratory bronchioles, whereas IV administration leads to a more perivascular distribution. IV injection of these particles leads to embolization of small pulmonary vessels and can result in pulmonary hypertension. The presence of pulmonary hypertension and talc in other organs strongly supports a vascular origin (8). These particles elicit a foreign body reaction that is often granulomatous. This is more commonly seen with talc and cellulose particulate (9). Characteristic radiologic patterns may be present on chest CT. Talc granulomas initially appear as diffuse micronodules. With progression of the disease, they coalesce to form large conglomerate masses in the upper lobes that resemble progressive massive fibrosis (10, 11). Lower-lobe emphysema may be seen, especially in methylphenidate abusers (5). Histologically, birefringent material was noted within the foreign body granulomas, and was largely what suggested the diagnosis. Recognition of pulmonary complications of IV drug use is potentially underappreciated, with this complication often recognized at autopsy. In a series of 851 autopsies performed in drug addicts from 1977–1996, pulmonary foreign bodies were found in 9.5% of cases, with the finding occurring more commonly in women (12). The long-term prognosis has been evaluated in a case series of 6 patients with a 10-year followup; despite cessation of IV drug use, all had progression of their respiratory disease, with 3 deaths occurring secondary to pulmonary disease during the followup period (13).

Talcosis can be the underlying etiology for pulmonary hypertension considered to be idiopathic. A high level of clinical suspicion is required because often the history of IV drug use with oral medications is not volunteered by patients. In a case series of 9 patients with biopsy-confirmed pulmonary talcosis, 5 had a previous diagnosis of idiopathic pulmonary hypertension (14).

Diverse organ involvement as a result of embolization of filler material from injection use of oral medications has been reported in the literature. The extent of systemic involvement is frequently noted only at autopsy. Terminology has been proposed to describe this as systemic angiocentric granulomatosis. Cerebral involvement due to embolization has been confused with multiple sclerosis in a previous case report (15). In a separate case report, a patient experienced a stroke after injecting methylphenidate, with an autopsy performed months later demonstrating foreign body granulomas present in the brain (16). Cerebral angiogram abnormalities have been noted in patients with a history of drug abuse with areas of constriction and occlusion. This may further complicate separating the differential diagnosis with CNS vasculitis (17). Further retinal involvement due to embolization has been identified (18, 19), which highlights the potential that our patient's initial ocular involvement was the result of embolization.

While there is no established treatment, cessation of IV injection is certainly warranted. Steroids and immunosuppressants have been tried but are not effective (20). Pulmonary hypertension is managed with vasodilators.

This case posed a diagnostic dilemma, with complex and seemingly disparate findings. It was ultimately the identification of granulomas with polarizable foreign material in the lung that prompted the diagnosis. The diagnosis of CNS vasculitis was questioned, and it was determined that the disease manifestations were secondary to embolization of exogenous material leading to pulmonary hypertension and CNS embolization via the patent foramen ovale. Furthermore, the concern regarding disseminated Actinomyces at the initial presentation was thought to be secondary to the immunosuppression caused by treatment for CNS vasculitis.

Access and familiarity with narcotic drugs is one reason that health care professionals are at high risk for becoming dependent. Many erroneously believe that they have the ability and control to monitor the use of medications because of their experience with administering medications to patients. The American Nurses Association estimates that 10–20% of nurses have substance abuse problems and that 6–8% abuse alcohol or other drugs (21). The recovery rate is high (85–90%), but the relapse rate in different studies varies from 25–50% (22). Recognizing the complications of misuse of prescription medications is critical, as 7 million people reported use of prescription drugs for nonmedical indications in the past month in 2010. Furthermore, in high school seniors, misuse of prescription and over-the-counter medications is second only to marijuana in types of drug use (23). Our patient had a history of abuse and had completed rehabilitation, but relapsed due to increasing personal stressors. During the evaluation of patients with pulmonary infiltrates with pulmonary hypertension, injection drug use must be considered.

FINAL DIAGNOSIS

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. PATIENT'S COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

Talcosis causing secondary pulmonary hypertension and central nervous system infarcts secondary to systemic embolization through a patent foramen ovale.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. PATIENT'S COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Chowdhary had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Krause, Maleszewski, Chowdhary.

Acquisition of data. Krause, Boland, Maleszewski, Gilbertson, Chowdhary.

Analysis and interpretation of data. Krause, Boland, Maleszewski, Chowdhary.

REFERENCES

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. PATIENT'S COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES